1. Updates oN Novel Oral Anticoagulant Reversal
Kaili Donahue, PharmD, BCPS
Clinical Pharmacist Specialist – Emergency Medicine
Saint Francis Hospital, Tulsa, OK

2. Disclosure
Under guidelines established by the Accreditation Council for Pharmacy Education, disclosure must be made regarding financial relationships with commercial interests within the last 12 months.
I have no relevant financial relationships or affiliations with commercial interests to disclose.

3. Objectives
At the completion of this activity, pharmacists will be able to:
Discuss novel oral anticoagulant risk of hemorrhage
Select appropriate reversal agent for hemorrhage associated with novel oral anticoagulants
Examine available evidence for use of andexanet alfa
At the completion of this activity, pharmacy technicians will be able to:
Discuss pharmacology of novel anticoagulants including common and severe side effects.
Identify reversal agents for hemorrhage associated with novel oral anticoagulants.

4. Pre-Assessment
Which factor-Xa inhibitor is contraindicated in NVAF patients with CrCl > 95 mL/min due to increased risk in ischemic stroke?
Edoxaban
Apixaban
Warfarin
Betrixaban

5. Pre-Assessment
What is the name of the available reversal agent for dabigatran?
4F-PCC
Phytonadione
Idarucizumab
Andexanet alfa

6. Pre-Assessment
Inhibiting tissue factor pathway inhibitor (TFPI) was an unintended consequence of coagulation factor Xa (recombinant), inactivated-zhzo. Which side effect of coagulation factor Xa (recombinant), inactivated-zhzo is thought to be caused by TFPI inhibition?
Sepsis
Bleeding
Thrombosis
Fever

7. Definitions NVAF = non-valvular atrial fibrillation
VTE = venous thromboembolism
ICH = intracranial hemorrhage
LMWH = low-molecular-weight heparin
VKA = vitamin-K antagonist
ISTH = International Society for Thrombosis and Haemostasis
NPSG = National Patient Safety Goal
4F-PCC = 4-factor prothrombin complex concentrate
DOAC = direct-acting oral anticoagulants
ISMP = Institute of Safe Medication Practices
Hgb = hemoglobin
PRBC = packed red blood cells
TFPI = Tissue Factor Pathway Inhibitor

8. History
Warfarin and aspirin as mainstay for stroke prevention and VTE treatment for decades
Routine laboratory monitoring
Lengthy onset and offset of anticoagulant effect
Numerous drug and food interactions
High incidence of bleeding complications
FDA-approved 5 new oral anticoagulants since 2010
3 new reversal agents
ASHP 2015
Include nomenclature “nomenclature of these newer anticoagulants
has been extensively discussed since their approval, but the
Scientific and Standardization Committee (SSC) for Control of
Anticoagulation of the International Society for Thrombosis
and Haemostasis (ISTH) recently recommended DOAC as
the acronym for non-vitamin K oral anticoagulants, including
direct factor Xa inhibitors and direct factor IIa (thrombin)
inhibitors.” PSAP for anticoag

9. Anticoagulant Adverse Effects
CDC found anticoagulants account for 17.6% of all ED visits for outpatient adverse drug effects
More than any other class of drugs!
NPSG July 2019
Anticoagulant safety now includes DOACs
Anticoagulants accounted for ED visits from 2013 to 2014 associated with adverse drug events
From 2009 to 2014, oral anticoagulant use increased by approximately 38%,21 whereas the proportion of ED visits for anticoagulants increased by 57%
Warfarin was implicated in an estimated 85.7% (95% CI, 82.8%-88.6%) of ED visits for anticoagulant adverse drug events among older adults (aged ≥65 years) and target-specific oral anticoagulants (apixaban, dabigatran, and rivaroxaban) were implicated in an estimated 12.0% (95% CI, 8.9%-15.1%) of ED visits for anticoagulant adverse drug events. Among older adults, the hospitalization rate for ED visits for adverse drug events from target-specific oral anticoagulants (55.7%; 95% CI, 45.6%-65.9%) was similar to the rate for warfarin (49.8%; 95% CI, 42.9%-56.7%).
November 22/29, 2016
US Emergency Department Visits for Outpatient Adverse Drug Events,
Nadine Shehab, PharmD, MPH1; Maribeth C. Lovegrove, MPH1; Andrew I. Geller, MD1; et al Kathleen O. Rose, BSN2; Nina J. Weidle, PharmD3; Daniel S. Budnitz, MD, MPH1
Author Affiliations Article Information  JAMA. 2016;316(20): doi: /jama
Shehab, Nadine, et al. "US emergency department visits for outpatient adverse drug events, " Jama (2016):

10. Timeline Warfarin (Coumadin) 1954 Dabigatran (Pradaxa) 2010
Rivaroxaban (Xarelto)
2011
Edoxaban (Savaysa)
2015
Betrixaban (Bevyxxa)
2017
Apixaban (Eliquis)
2012
1983
Phytonadione
2015
Idarucizumab (Praxbind)
2018
Coagulation Factor Xa
(recombinant), inactivated
– zhzo (Andexxa)
2013
Prothrombin Complex Concentrate
(Human) (Kcentra)

11. Direct Thrombin Inhibitors
Intrinsic System
(surface contact)
Extrinsic System
(tissue damage)
Warfarin
and
4-FPCC
XII
XIIa
Tissue Factor
Direct Thrombin Inhibitors XI
XIa
VIIa
VII IX
IXa
Factor Xa
Inhibitors
VIII
VIIIa X Xa V Va II
(Prothrombin)
IIa
(Thrombin)
Fibrinogen
FIBRIN
Activated vitamin K is required in the hepatic synthesis of activated clotting factors. Warfarin’s mechanism of action is complex, but includes inhibiting the enzyme vitamin-K-epoxide-reductase, which leads to decreased functional, activated vitamin K reserves, which leads to decreased synthesis of these vitamin-K dependent, activated clotting factors. Warfarin is the only available US-FDA-approved vitamin K antagonist.
Because the newer oral anticoagulants directly inhibit activated clotting factors, [Thrombin or clotting factor Iia for dabigatran and Xa for the Factor Xa inhibitors], they are jointly referred to as ‘DIRECT oral anticoagulants’ or ‘DOACs’.
Clotting Cascade
Adapted from Managing and Reversing Direct Oral Anticoagulants: A Discussion Guide (2015)

12. DOAC Generalizations All noninferior to LMWH/VKA for recurrent VTE
Lower (apixaban, rivaroxaban) or similar (edoxaban, dabigatran) bleeding rates
All at least as effective as VKA for stroke prevention in NVAF
Less ICH, reduced mortality
Increased risk of GI bleeding (except apixaban)
Betrixaban labeled for VTE prophylaxis only
Dosing varies widely based on indication, renal function, drug interactions, etc

13. Dabigatran Only oral-direct thrombin inhibitor
Similar or increased risk of bleeding vs warfarin
GI side-effects
Most reliant on renal elimination
Drug-interactions (P-glycoprotein)
RE-ALIGN trial stopped early for HARM
Dilute Thrombin Time or Ecarin Clotting Time
WARNING
Premature discontinuation of dabigatran increases the risk of thrombotic events.
Spinal/Epidural hematoma may occur if receiving neuraxial anesthesia or spinal puncture.
Pradaxa (dabigatran) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; February 2019

14. Rivaroxaban New CAD indication (COMPASS trial)
Lower major bleeding in VTE, but increased GIB in NVAF
p-GP and CYP3A4 interactions
Once-daily dosing
Prothrombin time or Anti-Xa
GALILEO is a randomized, open label, active-controlled, multicentre phase III trial to evaluate clinical outcomes after successful TAVR in subjects randomized to either a XARELTO-based anticoagulation strategy or an antiplatelet-based strategy. The first group received XARELTO 10 mg once daily and ASA mg once daily for 90 days, followed by maintenance with XARELTO 10 mg once daily. The comparator group was given clopidogrel 75 mg and ASA mg once daily for 90 days, followed by ASA alone.
The primary efficacy endpoint is a composite of all-cause death, stroke, systemic embolism, myocardial infarction, PE, DVT, and symptomatic valve thrombosis. The primary safety endpoint is a composite of life-threatening or disabling and major bleeding events. Patients with atrial fibrillation were excluded from this trial.
In August 2018, the independent Data Safety Monitoring Board recommended stopping the trial, as a preliminary analysis of available data suggested a numerical imbalance between the two study groups in all-cause mortality, thromboembolic and bleeding events. The incidences in the XARELTO group (826 patients) and the antiplatelet group (818 patients), respectively, were 11.4% versus 8.8% for death or first thromboembolic events, 6.8% versus 3.3% for all-cause death and 4.2% versus 2.4% for primary bleeding events. These results are preliminary and based on incomplete data collection. The final study data will be assessed as soon as they are available, including an assessment of any implications for approved indications.
TAVR is performed in patients who need an aortic valve replacement but who are at too high a risk for a standard open heart valve surgery. Patients undergoing TAVR present with multiple clinical risk factors pertinent to the background disease of aortic valve stenosis.
WARNING
Premature discontinuation of rivaroxaban increases the risk of thrombotic events.
Spinal/Epidural hematoma may occur if receiving neuraxial anesthesia or spinal puncture.
Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals Inc; February 2019

15. Apixaban
Consistently decreased event rate and lower bleeding rates than warfarin
Least dependency on renal elimination
Pharmacokinetic data supported renal dosing
p-GP and CYP3A4 interactions
Twice-daily dosing
WARNING
Premature discontinuation of apixaban increases the risk of thrombotic events.
Spinal/Epidural hematoma may occur if receiving neuraxial anesthesia or spinal puncture.
Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; February 2019

16. Reduced efficacy in NVAF patients with CrCl > 95 mL/min
Edoxaban
Lower major bleeding in VTE, but similar bleeding in NVAF
Like dabigatran, parenteral anticoagulation > 5 days THEN begin VTE treatment with edoxaban
p-GP interactions
No renal impairment: Edoxaban blood levels are lower in patients with better renal function, averaging about 30% less in patients with CrCl >80 mL/minute and 40% less in patients with CrCl >95 mL/minute when compared to patients with CrCl >50 to ≤80 mL/minute (lexi)
WARNING
Reduced efficacy in NVAF patients with CrCl > 95 mL/min
Premature discontinuation of edoxaban increases the risk of thrombotic events.
Spinal/Epidural hematoma may occur if receiving neuraxial anesthesia or spinal puncture.
Savaysa (edoxaban) [prescribing information]. Parsippany, NJ: Daiichi Sankyo; February 2019

17. Betrixaban VTE prophylaxis only
APEX trial found significantly less VTE vs LMWH in hospitalized medical patients without an increase in bleeding
RRR = 0.26 [ ], P = .023
p-GP interactions
WARNING
Spinal/Epidural hematoma may occur if receiving neuraxial anesthesia or spinal puncture.
Bevyxxa (betrixaban) [prescribing information]. South San Francisco, CA: Portola Pharmaceuticals Inc; February 2019

18. DOAC Bleed Rates
Ruff, Christian T., et al. "Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials." The Lancet (2014):
van Es, Nick, et al. "Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials." Blood (2014):

19. Reversal Agents

20. General Management Assess bleed (any of following = major bleed)
Critical site of life-threatening
Hemodynamic instability
Clinically overt bleeding with Hgb decrease > 2 g/dL or requiring administration of >2 units PRBCs
Stop oral anticoagulant
Provide local therapy/manual compression
Supportive care
Assess and manage comorbidities that could be contributing to bleed
Consider surgical/procedural management
2017 ACC EDCP on mgmt of bleed
Tomaselli, Gordon F., et al. "2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways." Journal of the American College of Cardiology (2017):

21. 4-Factor Prothrombin Complex Concentrate (4F-PCC)
Blood coagulation factor replacement product
Factors II, VII, IX, X, protein C and S
Administer with vitamin K concurrently*
Lyophilized powder in single-use vials
Potency and Dosing per Factor IX nominal strength
500 IU/20 mLs
1000 IU/40 mLs
Onset: minutes
Duration: 6-8 hours*
Pretreatment INR
Units/kg
Maximum dose
INR 2-3.9 25
2500 units
INR 4-6 35
3500 units
INR > 6 50
5000 units
Administer by intravenous infusion at a rate of 0.12 mL/kg/min (~3 units/kg/min), up to a maximum rate of 8.4 mL/min (~210 units/min).
WARNING
ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS
Kcentra (prothrombin complex concentrate human) [prescribing information]. Kankakee, IL: CSL Behring; February 2019

22. 4-Factor Prothrombin Complex Concentrate (4F-PCC)
4F-PCC vs plasma for VKA reversal in Acute Major Bleeding (2013)
randomized, controlled, non-inferiority trial comparing 4F-PCC to plasma
4F-PCC
Plasma
Hemostatic Efficacy at 24 hours
(n=202)
72.4 % excellent or good
65.4 % excellent or good
Rapid INR Reduction at 30 minutes (<1.3)
62.2 %
(95% CI, 52.6 to 71.8)
9.6 %
(95% CI, 3.9 to 15.3)
Serious Adverse Events
(n=212)
32 (31.1 %)
2 treatment-related
26 patients(23.9 %)
4 treatment-related
Thromboembolic Events
8 (7.8 %)
7 (6.4%)
3 treatment-related
Mortality at 30 days
6 (5.8 %)
1 treatment-related
5 (4.6 %)
The median infusion time was >8 times
longer in the plasma group than the 4F-PCC group. Therefore,
there was a substantial difference between initiation of treatment
and the assessment time point. In a clinical context,
within 1 hour of the start of infusion, more than two thirds of
patients had INR ≤1.3 in the 4F-PCC group compared with
none in the plasma group.
the median volume of plasma administered in
this study was >8 times greater than the volume of 4F-PCC
(813.5 versus 99.4 mL).
Sarode, Ravi, et al. "Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study." Circulation (2013):

23. 4-Factor Prothrombin Complex Concentrate (4F-PCC)
4F-PCC vs plasma for VKA reversal in Urgent Surgical/Procedural needs (2015)
randomized, controlled, non-inferiority trial comparing 4F-PCC to plasma
4F-PCC
Plasma
Hemostasis during surgical or invasive procedure (n=168)
78/87 (90 %)
61/81 (75 %)
14.3% (2.8 to 25.8) (95 % CI)(p=0.0142)
Rapid INR Reduction at 30 minutes (<1.3)
(n=168)
48/87 (55 %)
8/81 (10 %)
45.3% (31.9 to 56.4) (95 % CI)(p=<0.0001)
Serious Adverse Events
(n=176)
22/88 (25 %)
3 treatment-related
23/88 (26 %)
Thromboembolic Events
6/88 (7 %)
7/88 (8 %)
−1.1% (-10 to 8) (95 % CI)(p=0.77)
Mortality at 45 days
3/88 (3 %)
8/88 (9 %)
1 treatment-related
Goldstein, Joshua N., et al. "Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial." The Lancet (2015):

24. 4-Factor Prothrombin Complex Concentrate
Meta-Analysis of PCC for DOAC acute bleeding management
10 nonrandomized, unblinded, single-arm case series 4FPCC received
Pooled Outcome
4FPCC (N=340)
Effective major bleeding management (ISTH criteria) (n=150)
0.69
(95% CI, 0.61 to 0.76)
Effective major bleeding management
(NON-ISTH criteria) (n=190)
0.77
(95% CI, 0.63 to 0.92)
Mortality (n=249)
0.16
(95% CI, 0.07 to 0.26)
Thromboembolic Events (n=240)
0.04
(95% CI, 0.01 to 0.08)
Piran, Siavash, et al. "Management of direct factor Xa inhibitor–related major bleeding with prothrombin complex concentrate: a meta-analysis." Blood advances 3.2 (2019):

25. Idarucizumab
Humanized, monoclonal antibody binding to dabigatran and metabolites
Supplied as cartons of (2) single-dose 2.5 gram/50 mL vials
Recommended dose: 5 gram IV infusion
Consecutively infuse (2) 2.5 gram vials no more than 15 minutes apart OR bolus injection (2) 2.5 gram vials
Onset: minutes
Duration: ~24 hours
Praxbind injection (idarucizumab) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; February 2019

26. Idarucizumab REVERSE-AD
Multicenter, prospective, open-label case series of 503 patients reversing dabigatran in life-threatening bleeding or need for urgent surgery
Primary Efficacy Outcomes
Median % reversal of anticoagulant effect in 4 hours (n=461)
100%
(95% CI, 100 to 100)
Group A (N= 310, n=203)
(uncontrollable bleeding)
Group B (N= 202, n=197)
(urgent procedure/surgery)
Restoration of hemostasis
67.7 % (134) confirmed bleeding cessation in 24 hours
Median time to hemostasis: 2.5 hours (95% CI, 2.2 to 3.9)
93.4 % normal hemostasis
5.1 % mildly abnormal
1.5 % moderately abnormal
Median time to procedure: 1.6 hours
Cessation of bleeding: 134 (n=203, 67.7%) of the non-ICH patients who had uncontrolled bleeding had confirmed bleeding cessation within 24 hours, with a median time of 2.5 hours
Clotting: Among the patients who underwent emergency surgery or urgent procedures (n=197), periprocedural hemostasis was assessed as normal in 93.4% (n=184) of patients, mild abnormal in 5.1% (n=10), and moderately abnormal in 1.5% (n=3) (PraxbindPI)
Use of blood products – patients could have received more than one treatment…
Total: 238/503 (47.3 %) (whole blood, FFP, cryo, PRBCs, platelets)
28 patients (5.6%) received plasma derivative (3FPCC, 4FPCC, FactorVIIa, aPCC)
Pollack Jr, Charles V., et al. "Idarucizumab for dabigatran reversal—full cohort analysis." New England Journal of Medicine (2017):

27. Idarucizumab
Reappearance of dabigatran was observed in 114 of 497 patients (23 %)
10 patients experienced recurrent or continual bleeding
9 of 503 patients received more than 5 grams of Idarucizumab
7 received a second dose, 1 received (two) additional doses, 1 received a second dose in error
Pollack Jr, Charles V., et al. "Idarucizumab for dabigatran reversal—full cohort analysis." New England Journal of Medicine (2017):

28. Idarucizumab REVERSE-AD Primary Safety Outcomes (N=503)
Group A (n= 310)
(uncontrollable bleeding)
Group B (n= 202)
(urgent procedure/surgery)
30-day mortality
13.5 %
12.6 %
5-day mortality
6.3 %
7.9 %
Anti-idarucizumab antibody formation (n=501)
28 (5.6 %)
19 pre-existing antibodies
9 developed during treatment
Thrombotic events within 30 days 14 10
Serious Adverse Events
66 (21.9 %)
51 (25.2 %)
Of the 503 dabigatran-treated patients in the entire study period, 101 patients died, 19 within the first day after idarucizumab dosing; each of these deaths could be attributed either as a complication of the index event or associated with co-morbidities.
reappearance of levels
above 20 ng per milliliter was observed in 114 of
497 patients (23.0%), mainly after 12 hours,
with 67 patients having elevated levels only at
the 24-hour measurement. These recurrent elevations were associated with recurrent or continued bleeding in 10 patients in group A and in no
patients in group B; of the 10 patients, 3 received
an additional dose of idarucizumab. At 24 hours,
the median idarucizumab concentration had
decreased to less than 1% of the peak median,
a finding consistent with the short half-life of
idarucizumab (Fig. S3 in the Supplementary
Appendix).10
Only 9 of the 503 patients (1.8%) received more
than 5 g of idarucizumab, including the 3 in group
A who had recurrent bleeding; 7 received a second
dose of idarucizumab and 1 received two additional doses because they had recurrent bleeding
or were undergoing a second urgent surgical procedure (Table 3). One patient received a second
dose in error.
Pollack Jr, Charles V., et al. "Idarucizumab for dabigatran reversal—full cohort analysis." New England Journal of Medicine (2017):

29. Andexanet alfa Coagulation factor Xa (recombinant), inactivated-zhzo
Original 2015 submission rejected due to lack of manufacturing details
Received FDA approval in May 2018
Conditional on post-marketing clinical benefit
Generation-2 manufacturing line approved December 2018
ANEXXA-4 trial published February 2019
U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Andexxa NDA approval letter, May 3, Retrieved February 28, 2019 from

30. Andexanet alfa Coagulation factor Xa (recombinant), inactivated-zhzo
Reversal of rivaroxaban or apixaban for life- threatening or uncontrolled bleeding
Acts a decoy protein to bind Factor Xa inhibitors
Also inhibits the activity of Tissue Factor Pathway Inhibitor (TFPI)
Supplied as cartons of (4) single-use 100 mg vials
active ingredient of ANDEXXA is a genetically modified variant of human Coagulation Factor Xa (FXa) produced by recombinant DNA technology in a Chinese Hamster Ovary (CHO) cell line.
WARNING
THROMBOEMBOLIC RISKS, ISCHEMIC RISKS,
CARDIAC ARREST, AND SUDDEN DEATHS
Andexxa (andexanet alfa) [prescribing information]. South San Francisco, CA: Portola Pharmaceuticals, Inc; February 2019

31. Andexanet alfa Coagulation factor Xa (recombinant), inactivated-zhzo
Dose
Initial IV Bolus
Following IV Infusion
Low Dose
400 mg at a target rate of 30 mg/min
4 mg/min for up to 120 min
High Dose
800 mg at a target rate of 30 mg/min
8 mg/min for up to 120 min
Factor Xa inhibitor
Last Dose
Dose < 8 hours or Unknown
> 8 hours
Rivaroxaban
< 10 mg
Low Dose
>10 / Unknown
High Dose
Apixaban
< 5 mg
> 5 mg / Unknown
Andexxa (andexanet alfa) [prescribing information]. South San Francisco, CA: Portola Pharmaceuticals, Inc; February 2019

32. Andexanet alfa Coagulation factor Xa (recombinant), inactivated-zhzo
Rapid Onset (minutes)
Half-life varies per dose: ~2 to 4 hours
Anti-Factor Xa activity increases to placebo levels ~ 2 hours after andexanet alfa infusion
“It is possible that further refinements in the administration of andexanet could lead to more complete reversal of anti–factor Xa activity and improved clinical outcomes.”
Siegal, Deborah M., et al. "Andexanet alfa for the reversal of factor Xa inhibitor activity." New England Journal of Medicine (2015):

33. ANNEXA-4
ANNEXA-4
Multicenter, prospective, open-label, single-group cohort study of 352 patients with acute major bleeding reversing factor Xa inhibitors
Inclusion:
> 18 years, acute major bleeding, received apixaban, rivaroxaban, edoxaban, enoxaparin (treatment dose) within previous 18 hours,
Exclusion:
Planned surgery within 12 hours of andexanet, ICH with GCS < 7, ICH with hematoma volume > 60 mL, expected survival of less than 1 month, thrombotic event in prior 2 weeks, use of VKA, dabigatran, PCC, Factor VIIa, whole blood, or plasma in prior 7 days
Many protocol deviations – enrollment criteria, dosing protocol, primary endpoint, etc
Connolly, Stuart J., et al. "Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors." New England Journal of Medicine (2019).

34. ANNEXA-4
ANNEXA-4
Multicenter, prospective, open-label, single-group cohort study of 352 patients with acute major bleeding reversing factor Xa inhibitors
Primary Efficacy Outcomes
Andexanet alfa (n=254, 72%)
Apixaban (n=134)
Rivaroxaban (n=100)
Enoxaparin (n=16)
% change from baseline Anti-Xa activity (n=250*)
92%
(95% CI, 91 to 93)
(95% CI, 88 to 94)
75%
(95% CI, 66 to 79)
% excellent or good hemostatic efficacy at 12 hours (n=249^)
83%
(95% CI, 77 to 90)
80%
(95% CI, 72 to 88)
87%
(95% CI, 69 to 100)
*The four patients in the efficacy population who received edoxaban are not shown for the subgroup according to drug.
^five patients in the efficacy population in whom hemostatic efficacy could not be adjudicated owing to administrative reasons
The
sample was adjusted to 350 patients in protocol
amendment 4 (January 2017) to meet new regulatory
requirements for sufficient numbers of
patients for each factor Xa inhibitor and to have
at lea
There were 254 patients
(72%) who met the criteria for the efficacy
population (adjudicated to meet the criteria
for bleeding severity and with baseline anti–
factor Xa activity of ≥75 ng per milliliter, or
≥0.25 IU per milliliter for those receiving enoxaparin).st 120 patients with intracranial hemorrhage
Connolly, Stuart J., et al. "Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors." New England Journal of Medicine (2019).

35. ANNEXA-4
ANNEXA-4
Multicenter, prospective, open-label, single-group cohort study of 352 patients with acute major bleeding reversing factor Xa inhibitors
Primary Safety Outcomes
Andexanet alfa (n=352, 100%)
<6 days after bolus
6 to 14 days after bolus
15 to 30 days after bolus
> 1 Thrombotic event within 30 days (n=34, 10%) 11 12
Death within 30 days (n=49, 14%) 8 21 20
Restart of any anticoagulation (n=220, 62%)
145 (41%)
46 (13 %)
29 (8 %)
Connolly, Stuart J., et al. "Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors." New England Journal of Medicine (2019).

36. Coagulation factor Xa (recombinant), inactivated-zhzo
Intrinsic System
(surface contact)
Extrinsic System
(tissue damage)
Warfarin
and
4-FPCC
XII
XIIa
Tissue Factor
Direct Thrombin Inhibitors XI
XIa
Tissue Factor Pathway Inhibitor
VIIa
VII IX
IXa
Factor Xa
Inhibitors
VIII
VIIIa
Coagulation factor Xa (recombinant), inactivated-zhzo X Xa V Va II
(Prothrombin)
IIa
(Thrombin)
Fibrinogen
FIBRIN
Activated vitamin K is required in the hepatic synthesis of activated clotting factors. Warfarin’s mechanism of action is complex, but includes inhibiting the enzyme vitamin-K-epoxide-reductase, which leads to decreased functional, activated vitamin K reserves, which leads to decreased synthesis of these vitamin-K dependent, activated clotting factors. Warfarin is the only available US-FDA-approved vitamin K antagonist.
Because the newer oral anticoagulants directly inhibit activated clotting factors, [Thrombin or clotting factor Iia for dabigatran and Xa for the Factor Xa inhibitors], they are jointly referred to as ‘DIRECT oral anticoagulants’ or ‘DOACs’.
Coagulation factor Xa (recombinant), inactivated-zhzo
Acts as a decoy for Factor Xa inhibitors to bind
Lacks natural procoagulant properties of endogenous Factor Xa
Also binds and inhibits Tissue Factor Pathway Inhibitor (TFPI)
Unanticipated procoagulant property
Siegal, Deborah M., et al. "Andexanet alfa for the reversal of factor Xa inhibitor activity." New England Journal of Medicine (2015):

37. Balancing Risk and Benefit
Efficacy and Safety Comparison for reversing bleed on DOAC
4FPCC
Idarucizumab
Andexanet alfa
Effective major bleeding management (ISTH criteria)
69 – 77 %
67 – 93 %
80 – 87%
Thromboembolic Events
4 %
5 %
10 %
Death at 30 or 45 days
16 %
13 %
14 %
Consider:
Rebound of anticoagulant
Emergent need/availability
Cost
Patient population
Need for surgery
Restarting Anticoagulation
RISK
BENEFIT

38. Reversal Agent Comparison
4F-PCC
Idarucizumab
Andexanet alfa
Off-label for DOAC reversal
Limited evidence
Dosing errors may occur
Dabigatran only
Dosing errors may occur
Thrombotic event rate
Cost
$29, $59,400
4F-PCC vs Andexanet alfa
Randomized, controlled trial in ICH with DOAC
EXPECTED 2023

39. Post-Assessment
Which factor-Xa inhibitor is contraindicated in NVAF patients with CrCl > 95 mL/min due to increased risk in ischemic stroke?
Edoxaban
Apixaban
Warfarin
Betrixaban

40. Post-Assessment
What is the name of the available reversal agent for dabigatran?
4F-PCC
Phytonadione
Idarucizumab
Andexanet alfa

41. Post-Assessment
Inhibiting tissue factor pathway inhibitor (TFPI) was an unintended consequence of coagulation factor Xa (recombinant), inactivated-zhzo. Which side effect of coagulation factor Xa (recombinant), inactivated-zhzo is thought to be caused by TFPI inhibition?
Sepsis
Bleeding
Thrombosis
Fever

42. Conclusion DOACs have variable rates hemorrhage
Overall, lower incidence than warfarin
Reversal agents for DOACs are now available
Newly-approved andexanet alfa (coagulation factor Xa (recombinant), inactivated-zhzo) offers reversal agent for apixaban or rivaroxaban

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