1. ACCP Cardiology PRN Journal Club

2. Announcements Thank you attending the ACCP Cardiology PRN Journal Club
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3. Dr. Quyen Dau
Completed Bachelor of Science in both Biology and Psychology from Baylor University
Completed her Doctorate of Pharmacy from Texas A&M College of Pharmacy
Completed a PGY1 residency at CHI-St. Luke’s Health-Baylor St. Luke’s Medical Center in Houston, TX where she is currently a PGY2 cardiology resident

4. Dr. Toby Trujillo
Completed his Doctorate of Pharmacy and pharmacy practice residency at the University of California-San Francisco
Completed a cardiovascular pharmacotherapy fellowship at the University of Arizona College of Pharmacy
Currently an Associate Professor and clinical specialist at the University of Colorado Skaggs School of Pharmacy and Medical Campus

5. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors (ANNEXA-4)
Quyen Dau, PharmD
PGY-2 Cardiology Pharmacy Resident
CHI St. Luke’s Health-Baylor St. Luke’s Medical Center
Houston, Texas
Presenter
Toby C. Trujillo, PharmD, FCCP, FAHA, BCPS-AQ Cardiology| Associate Professor
University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
University of Colorado Anschutz Medical Campus
Clinical Specialist - Anticoagulation/Cardiology
University of Colorado Hospital
Mentor

6. Background
Direct oral anticoagulants (DOACs) reduce the risk of bleeding relative to warfarin
Concerns remain regarding the management of bleeding related to DOAC use
Currently only one agent is available for urgent reversal of dabigatran-associated emergent bleeding
No agent has yet been approved for rapid reversal of anti-factor Xa inhibitors
Brown et al. Critical Care. 2016;20:273
Pollack CV, Reilly PA, Eikelbloom J, et al. N Engl J Med. 2015;373:511-20

7. Andexanet Alfa Pharmacology
Recombinant modified human factor Xa decoy protein that is catalytically inactive
Retains the ability to bind factor Xa inhibitors in the active site with high affinity
Designed to neutralize the anticoagulant effect of both direct and indirect factor Xa inhibitors
Milling TJ, Kaatz S. Am J Med.2016;129(11S):S80-S88.

8. ANNEXA-A/R Trial
Evaluate the ability of andexanet to reverse anticoagulation with apixaban or rivaroxaban and safety of andexanet in healthy older volunteers
Objective
Randomized, double-blind placebo controlled study
Part 1: Andexanet bolus alone
Part 2: Andexanet bolus followed by a continuous 120 minute infusion
Study Design
Primary endpoint: Percent change in anti-factor Xa activity from baseline to nadir
Endpoints
Siegal D et al. N Engl J Med. 2015; 373:25

9. ANNEXA-A/R: Study Treatment
Apixaban 5 mg twice daily for 3.5 days
3 hours after the last dose of apixaban
Andexanet 400 mg IV bolus or 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes
Apixaban
Rivaroxaban 20 mg once daily for 4 days
4 hours after the last dose of rivaroxaban
Andexanet 800 mg IV bolus or as an 800-mg IV bolus followed by continuous infusion of 8 mg/min for 120 minutes
Rivaroxaban

10. ANNEXA-A/R Results Apixaban Rivaroxaban
Part 1
bolus only
Part 2
bolus+infusion
Adexanet
Placebo
Andexanet N 24 9 23 8 27 14 26 13
Primary Endpoint
Mean change (SD) in anti-FXA activity from baseline to nadir post-bolus (Part1) or post infusion (Part 2)
-198.7
(60.8)
-42.5
(24.5)
-160.6
(49.3)
-63.2
(18.1)
-292.2
(75.9)
-46.5
(42.2)
-324.5
(89.2)
-143.4
(58.8)
% change (SD) in anti-FXa activity
-93.9
(1.7)
-20.7
(8.6)
-92.3
(2.8)
-32.7
(5.6)
-92.2
(10.7)
-18.4
(14.7)
-96.7
(1.8)
-44.8
(11.7)
p-value % change (vs. placebo)
<0.001
There were no serious or severe adverse events, and no thrombotic events were reported.

11. ANNEXA-A/R: Conclusion
Andexanet rapidly restored factor Xa activity and thrombin generation and reduced unbound factor Xa inhibitor concentrations in apixaban and rivaroxaban treated older patients
Transient elevations in D-Dimer and prothrombin fragments 1 and 2 above normal ranges were noted in subgroup of patients, raising a concern for prothrombotic state

12. ANNEXA-4
Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors

13. ANNEXA-4: Objective
Evaluate the use of andexanet in patients with acute major bleeding that was potentially life-threatening

14. Study Design
Ongoing, multicenter, prospective, open label, single-group study
April 10, 2015-June 17, 2016
20 centers in the United States, 1 center in the United Kingdom, and 1 center in Canada

15. Annexa-4: Patient Population
Inclusion Criteria
Exclusion Criteria
At least 18 years old
Received one of the factor Xa inhibitors within 18 hours
Apixaban
Rivaroxaban
Edoxaban
Enoxaparin (at least 1 mg/kg/day)
Surgery within less than 12 hours after presentation
Except minimally invasive
Intracranial hemorrhage in patients with Glasgow Coma Scale score <7 or estimated intracerebral hematoma volume of more than 60 mL
Expected survival of less than 1 month
Major thrombotic event within 2 weeks before enrollment
Received of vitamin K antagonist, dabigatran, prothrombin complex, or whole blood* or plasma within 7 days before screening
*Whole blood did not include packed red blood cells or platelets

16. Acute Major Bleeding Definition
Potentially life-threatening acute overt bleeding with signs and symptoms of hemodynamic compromise
Severe hypotension, poor skin perfusion, mental confusion, low cardiac output that could not be explained
Acute overt bleeding with:
Hemoglobin decrease of at least 2 g/dL
Hemoglobin ≤ 8 g/dL without baseline hemoglobin
Investigators opinion that hemoglobin level would fall to ≤ 8 g/dL with resuscitation
Acute symptomatic bleed in critical organs
Retroperitoneal, intraarticular, pericardial, intracranial, intramuscular

17. Dose Selection
Acute major bleeding ≤ 18 hours of last dose of apixaban, edoxaban, rivaroxaban, or enoxaparin
Andexanet IV bolus and infusion
All patients receiving apixaban and those patients who received rivaroxaban >7 hours ago
Bolus 400 mg + Infusion 480 mg
@ 4 mg/min
Patients who received enoxaparin, edoxaban or a dose of rivaroxaban within ≤7 hours or at an unknown time*
Bolus 800 mg + Infusion mg/min
* If there is a delay between medical presentation and start of andexanet of more than 7 hours, the patient received the dose for rivaroxaban >7 hours ago

18. Efficacy Populations and Outcomes
Coprimary outcomes*
Percent change in the anti-factor Xa activity
Rate of excellent or good hemostatic efficacy in 12 hours after infusion
*Only patients whose baseline anti-factor Xa activity was ≥ 75 ng/mL or ≥0.5 IU/mL for enoxaparin were included in the efficacy analysis
Sarode R et al. Circulation. 2013; 128:

19. Hemostatic Efficacy
The independent adjudication committee reviewed each case to determine hemostatic efficacy on the basis of pre-determined criteria
Specific efficacy criteria for each type of bleed

20. Rating System for Effective Hemostasis Bleeding Type
Excellent (effective)
Good (effective)
Poor/none (not effective)
Visible
Cessation of bleeding ≤ 1 hour after end of infusion AND no plasma, coagulation factor or blood products (excludes pRBCs)
Cessation of bleeding between >1 AND ≤ 4 hours after the end of infusion and ≤ 2 units plasma, coagulation factor or blood products (excludes pRBCs)
Cessation of bleeding >4 hours after the end of the infusion AND/OR >2 units plasma, coagulation factor or blood products (excludes pRBCs)
Intracerebral
hematoma
≤20% increase in hematoma volume
compared to baseline on a repeat CT or MRI
scan performed at both the 1 and 12 hour post
infusion time points
>20% but ≤35% increase in hematoma
volume compared to baseline on a repeat CT or MRI scan at +12-hour time point
>35% increase in hematoma volume on a CT or MRI compared to baseline on a repeat CT or MRI scan at +12-hour time point

21. Safety Populations and Outcomes
Objective*
To evaluate the overall safety of andexanet, including adjudicated thromboembolic events and antibodies to factor X, factor Xa, and andexanet
*All patients who received andexanet were included in the safety assessment

22. Statistical Analysis
Data were reported as means (±SD) or medians and interquartile ranges for continuous variables and frequencies for categorical variables

23. Bleeding and laboratory assessment
ANNEXA-4: Study Design
Safety and Follow up
IV Bolus
2-hr IV infusion
4 hrs
8 hrs
12 hrs
3 days
30 days
Baseline
Bleeding and laboratory assessment

24. Baseline Characteristics
Efficacy Population
(N=47)
Safety Population
(N=67)
Age-yr
77.1±10.1
77.1±10.0
Male sex-no. (%)
24 (51)
35 (52)
White race-no. (%)
36 (77)
54 (81)
Time from presentation until andexanet bolus-hr
4.8±1.8
4.8±1.9
Estimated Creatinine Clearance-no. (%)
<30 mL/min
30-60 mL/min
≥60 mL/min
Missing data
4 (9)
25 (53)
17 (36)
1 (2)
6 (9)
31 (46)
26 (39)
4 (6)
Indication for for Anticoagulation-no. (%)
Atrial fibrillation
Venous thromboembolism
Atrial fibrillation and venous
32 (68)
12 (26)
3 (6)
47 (70)
15 (22)
5 (7)
Medical history-no. (%)
Myocardial infarction
Stroke
Deep vein thrombosis
Pulmonary embolism
Heart failure
Diabetes mellitus
7 (15)
15 (32)
16 (34)
34 (72)
19 (40)
13 (19)
17 (25)
20 (30)
49 (73)
23 (34)

25. Baseline characteristics
Factor Xa Inhibitor
Efficacy Population
N=47
Safety Population
N=67
Rivaroxaban, N
Median daily dose (IQR)-mg
Time from last dose to andexanet bolus
Baseline anti-factor Xa activity-ng/mL
Median unbound fraction of the plasma level (IQR)- ng/mL 26
20 (20-20)
12.0±4.1
297.0±171.0
19.3 ( ) 32
20 (15-20)
12.8±4.2
247±186.0
16.7 ( )
Apixaban, N 20
5 (5-10)
11.0±4.7
174.5±97.0
10.5 ( ) 31
12.1±4.7
137.7±102.3
9.4 ( )
Enoxaparin, N 1
200
13.1
0.6 4
90 (80-150)
10.8±3.5
0.4±0.2

26. Characteristics of Acute Major Bleeding Episodes
Efficacy Population
N=47
Safety Population
N=67
Gastrointestinal bleeding-no./total no. (%)
Upper
Lower
Unknown
25/47 (53)
7/25 (28)
8/25 (32)
10/25 (40)
33/67 (49)
9/33 (27)
10/33 (30)
14/33 (42)
Intracranial bleeding-no./total no. (%)
Baseline score on Glasgow Coma Scale
Intracerebral site-no./total no. (%)
Subdural site
Subarachnoid site
20/47 (43)
14.1±1.7
12/20 (60)
7/20 (35)
1/20 (5)
28 /67 (42)
14/28 (50)
11/28 (39)
3/28 (11)
Other bleeding site
Nasal
Pericardial, pleural, retroperitoneal
Genital or urinary
Articular
2/47 (4)
1/2 (50)
6/67 (9)
1/6 (17)
3/6 (50)
Clinical outcome
Death
Thromboembolic event
7/47 (15)
7/14 (15)
10/67 (15)
12/67 (18)
The primary site of bleeding was gastrointestinal in 33 patients or 49%, intracranial in 28 patients or 42% with other bleeding sites in 6 patients or 9% of the total patients.

27. Anti-Factor Xa Activity and Percent Change from Baseline Rivaroxaban

28. Anti-Factor Xa Activity and Percent Change from Baseline Apixaban

29. Hemostatic Efficacy at 12 hours

30. Thromboembolic events or Death During the 30-Day Study Period

31. N=67
Death-no. (%)
Cardiovascular causes
Non-cardiovascular causes
10 (15%)
6 (9%)
4 (6%)

32. Thromboembolic events or Death During the 30-Day Study Period

33. Thromboembolic events or Death During the 30-Day Study Period
Thromboembolic events-no. (%)
Myocardial infarction
Stroke
Deep-vein thrombosis
Pulmonary Embolism
12 (18%)
1 (1.5%)
5 (7.5%)
7 (10.4%)
Death-no. (%)
Cardiovascular causes
Non-cardiovascular causes
10 (15%)
6 (9%)
4 (6%)
Anticoagulation was resumed in 18 patients within 30 days
Therapeutic dose of anticoagulation was restarted before the event in only 1 of 12 patients with a thrombotic event
Four patients had thrombotic event within 3 days after andexanet treatment
The rest of the thrombotic events occurred between 4 and 30 days.

35. Conclusion
Andexanet rapidly reversed anti-factor Xa activity and was not associated with serious side effects
Effective hemostasis was achieved 12 hours after infusion of andexanet in 79% of patients.
In this preliminary report of an ongoing cohort study in patients with acute major bleeding associated with the use of factor Xa inhibitors, andexanet rapidly reversed anti–factor Xa activity and was not associated with
serious side effects. Effective hemostasis was achieved 12 hours after an infusion of andexanet in 79% of the patients. Thrombotic events occurred in 18% of the patients in the safety population, and 15% of the patients died during follow-up.

36. Critique Strengths Weaknesses
Restricted to patients with severe bleeding
Included patients only with anti-factor Xa activity 75 ng/mL or higher
Difficult to assess the clinical benefit without a control group
Hemostatic efficacy was assessed at 12 hours
Time from presentation until andexanet bolus was ~5 hours
Validated chromogenic assay of factor Xa enzymatic activity not readily available at many institutions
Validation of quality assays
Amount of pRBCs given not reported

37. Impact on Clinical Practice: Critical Considerations
If FDA approved, formulary or non-formulary?
Protocol for the management of bleeding and reversal
Acute bleeding
Reversal for surgery
Dosing for patients with renal impairment
Should a re-dose of andexanet be given if clinically relevant bleeding re-occurs?

38. Acknowledgments Journal Club Mentor: Program Director:
Toby C. Trujillo, PharmD, FCCP, FAHA, BCPS-AQ Cardiology
Program Director:
Maryam Bayat, PharmD, BCPS-AQ Cardiology
ACCP Cardiology PRN Journal Club Coordinators:
Carrie S. Oliphant, PharmD, FCCP, BCPS-AQ Cardiology
Zachary Noel, PharmD, BCPS

39. References
Brown et al. Nonvitamin K antagonist oral anticoagulant activity: challenges in measurement and reversal. Critical Care. 2016; 20:273
Pollack CV, Reilly PA, Eikelbloom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511-20
Milling TJ, Kaatz S. Preclinical and clinical data for factor Xa and “universal” reversal agents. Am J Med.2016;129(11S):S80-S88
Siegal D et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015; 373:25
Sarode R et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013; 128:
Connolly S et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med DOI: /NEJMoa

40. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors (ANNEXA-4)
Quyen Dau, PharmD
PGY-2 Cardiology Pharmacy Resident
CHI St. Luke’s Health-Baylor St. Luke’s Medical Center
Houston, Texas
Presenter
Toby C. Trujillo, PharmD, FCCP, FAHA, BCPS-AQ Cardiology| Associate Professor
University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
University of Colorado Anschutz Medical Campus
Clinical Specialist - Anticoagulation/Cardiology
University of Colorado Hospital
Mentor

41. Thank you for attending!
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