1. ACCP Cardiology PRN Journal Club

2. Announcements Thank you attending the ACCP Cardiology PRN Journal Club
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Next Journal Club September 28th

3. Presenter: Dr. Stephanie Dwyer, PharmD
Current position: PGY2 Cardiology Resident at the University of Illinois Hospital and Health Sciences System in Chicago
Prior training: Completed her PharmD at University of Illinois at Chicago’s satellite campus in Rockford, IL in She completed PGY1 at Captain James A. Lovell Federal Health Care Center in North Chicago, IL.

4. Mentor: Dr. Matthew Lillyblad, PharmD, BCPS-AQ Cardiology
Current Position: Pharmacy Coordinator for Cardiology and Critical Care at Abbott Northwestern Hospital in Minneapolis, Minnesota as well as the Residency Program Director for the PGY2 Pharmacy Residency in Cardiology.
Prior experience: Matt earned his PharmD from the University of Minnesota-Twin Cities in 2010, completed his PGY1 pharmacy residency at Abbott Northwestern Hospital in 2011 and went on to be the inaugural resident for PGY2 Cardiology Residency Program at Abbott Northwestern in 2012.  Matt’s professional experience has spanned the continuum of cardiology care, from the intensive care unit to the cardiology clinic.  He has led numerous initiatives for safe and effective use of anticoagulants at the department, hospital, and health system levels.

5. Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors Apixaban (ANNEXA-A) and Rivaroxaban (ANNEXA-R)
Stephanie Dwyer, PharmD
PGY2 Cardiology Pharmacy Resident
University of Illinois College of Pharmacy
Presenter
Matthew Lillyblad, PharmD, BCPS-AQ Cardiology
Clinical Pharmacy Coordinator – Cardiology and Critical Care
Clinical Pharmacy Specialist – Advanced Heart Failure
PGY2 Resident Program Director – Cardiology
Mentor
September 13th 2016

6. I have no actual or potential conflicts of interest to disclose
Disclosures
I have no actual or potential conflicts of interest to disclose

7. Background
Factor Xa inhibitors are FDA-approved for the treatment of VTE, secondary prevention of VTE, non-valvular atrial fibrillation, and DVT prophylaxis after orthopedic surgery
Factor Xa inhibitors: apixaban, rivaroxaban, edoxaban
Complete reversal of anticoagulation may be necessary in certain situations
Life threatening hemorrhage
Emergent surgery
Apixaban [package insert]. Available at
Rivaroxaban [package insert]. Available at
Edoxaban [package insert]. Available at

8. Clotting Cascade Andexanet alfa Vitamin K PCC Idarucizumab Vitamin K
Nat Rev Cardiol May;11(5):

9. Andexanet Alfa (AndexXa®)
Recombinant modified human factor Xa decoy protein
Catalytically inactive
Binds to factor Xa inhibitors within vascular space at their active site
High affinity and a 1:1 stoichiometric ratio
Enhances activity of endogenous factor Xa and attenuates levels of anticoagulant activity
Half-life: ~1 hour
Int J Cardiol. 2016;214:292-8.
N Engl J Med. 2015;373(25):

10. ANNEXA-A and ANNEXA-R
Randomized, double-blind, placebo-controlled, phase III trial
3:1 ratio (ANNEXA-A) and 2:1 ratio (ANNEXA-R) to receive andexanet alfa or placebo
Two sites:
ANNEXA-A: Celerion in Tempe, AZ
ANNEXA-R: West Coast Clinical Trials in Cypress, CA
Funded by: Portola Pharmaceuticals
N Engl J Med. 2015;373(25):

11. Study Objective
Establish efficacy and safety of andexanet for the reversal of anticoagulation with apixaban or rivaroxaban in older healthy volunteers
N Engl J Med. 2015;373(25):

12. Study Treatment 145 healthy volunteers 50-75 years old Apixaban:
65 patients
Andexanet alfa: 48 patients
Placebo: patients
Rivaroxaban:
80 patients
Andexanet alfa: 53 patients
Placebo: patients
N Engl J Med. 2015;373(25):

13. Study Treatment ANNEXA-A ANNEXA-R 3 hours after last dose
Apixaban 5mg PO BID x 3.5 days
3 hours after last dose
Part 1: Andexanet 400mg IV bolus (30 mg/min)
Part 2: Andexanet 400mg IV bolus then 4mg per min continuous infusion x 120 min
Placebo
Rivaroxaban 20mg PO daily x 4 days
4 hours after last dose
Part 1: Andexanet 800mg IV bolus (30 mg/min)
Part 2: Andexanet 800mg IV bolus then 8mg per min continuous infusion x 120 min
Placebo
The dose is higher for rivaroxaban because of higher peak concentrations and larger volume of distribution
N Engl J Med. 2015;373(25):

14. Study Efficacy Endpoints
Primary Endpoint
Percent change in anti-factor Xa activity from baseline to nadir
Part 1: 2 minutes or 5 minutes after end of bolus (smaller value)
Part 2: smallest value between 10 minutes before and 5 minutes after end of continuous infusion
Secondary Endpoints
Proportion of patients with > 80% reduction in anti-factor Xa activity from baseline to nadir
Part 2: percent change in anti-factor Xa activity from baseline to post-bolus nadir
Change in unbound factor Xa inhibitor plasma from baseline to nadir
Change in thrombin generation from baseline to peak
Occurrence of an endogenous thrombin potential (ETP) above lower limit of baseline-derived range at its peak
N Engl J Med. 2015;373(25):

15. Study Efficacy Endpoints
Laboratory tests performed:
Anti-factor Xa activity (Coamatic Heparin, DiaPharma)
Apixaban: 4.0 – ng/mL
Rivaroxaban: 4.0 – ng/mL
Free anticoagulant fraction
Unbound factor Xa inhibitor plasma concentration > 4 ng/mL was associated with therapeutic effect
Thrombin generation
Endogenous thrombin potential (ETP)
Activated clotting time (ACT)
D-dimer (upper limit of normal = 0.5 mcg/mL FEU)
F1+2 (reference range = 41 – 372 pmol/L)
N Engl J Med. 2015;373(25):

16. Study Safety Endpoints
Adverse events
Clinical assessments for thrombotic events
D-dimer (UNL = 0.5 mcg/mL)
Prothrombin fragments 1 and 2 (UNL = 372 pmol/L)
Antibodies to andexanet, factor X, and factor Xa
Plasma samples with confirmed anti-drug antibodies were assessed with anti-factor Xa assay to check for potential neutralizing actvity
Assessed at days 15, 36, and 43 after andexanet/placebo administration
N Engl J Med. 2015;373(25):

17. Study Statistical Analysis
Modified intention-to-treat population
Participants who received any amount of andexanet or placebo and for whom baseline anti-factor Xa activity and anti-factor Xa level after anticoagulation were available
Endpoints compared with exact Wilcoxon rank-sum test
To control for Type I error, primary endpoint was tested for significance first
145 patients provided power of 99% with two-sided p-value of 0.05
N Engl J Med. 2015;373(25):

18. Study Results – Patient Characteristics
ANNEXA - A
ANNEXA - R
Apixaban
Rivaroxaban
Part 1
Bolus only
Part 2
Bolus + infusion
Andexanet
Placebo N 24 9 8 27 14 26 13
Age – yr
Median
60.0
58.0
56.0
58.5
53.5
57.0
Female sex, N (%)
11 (45.8)
3 (33.3)
7 (29.2)
3 (37.5)
9 (33.3)
6 (42.9)
11 (42.3)
6 (46.2)
BMI, Mean (SD)
26.7 (2.5)
27.4 (2.5)
27.5 (2.1)
27.8 (2.4)
27.0 (3.4)
25.9 (3.4)
27.8 (3.0)
27.6 (2.6)
Creatinine, Mean (SD) (mg/dL)
0.8 (0.2)
0.8 (0.1)
0.9 (0.2)
Race, N (%) White
24 (100)
9 (100)
21 (87.5)
8 (100)
22 (81.5)
10 (71.4)
20 (76.9)
8 (61.5)
Ethnicity, N(%) Hispanic or Latino
10 (41.7)
4 (44.4)
2 (25)
4 (28.6)
4 (30.8)
10 (38.5)
N Engl J Med. 2015;373(25):

19. Study Results – Primary Efficacy Endpoint
ANNEXA - A
ANNEXA - R
94 + 2% andexanet vs % placebo % andexanet vs % placebo
p < p < 0.001
N Engl J Med. 2015;373(25):

20. Study Results – Primary Efficacy Endpoint
ANNEXA - A
ANNEXA - R
% andexanet vs % placebo % andexanet vs % placebo
p < p < 0.001
N Engl J Med. 2015;373(25):

21. Study Results – Secondary Efficacy Endpoints
ANNEXA - A
ANNEXA - R
Mean Change in Thrombin Generation
nMmin andexanet vs nMmin andexanet vs
nMmin placebo; p < nMmin placebo; p < 0.001
N Engl J Med. 2015;373(25):

22. Study Results – Secondary Efficacy Endpoints
ANNEXA - A
ANNEXA - R
Mean Change in Thrombin Generation
nMmin andexanet vs nMmin andexanet vs
nMmin placebo; p < nMmin placebo; p < 0.001
N Engl J Med. 2015;373(25):

23. Study Results – Secondary Efficacy Endpoints
ANNEXA-A (all p < 0.001)
ANNEXA-R (all p < 0.001)
Part 1
Part 2
Number of patients with > 80% reduction in anti-factor Xa activity
24 (100%) andexanet vs. 0 (0%) placebo
23 (100%) andexanet vs. 0 (0%) placebo
26 (96.3%) andexanet* vs. 0 (0%) placebo
26 (100%) andexanet vs. 0 (0%) placebo
Mean (SD) change in concentration of unbound FXa inhibitor (ng/mL)
-9.3 (3.2) ng/mL andexanet vs (1.6) ng/mL placebo
-6.5 (2.8) ng/mL andexanet vs (1.2) placebo
-23.4 (6.2) ng/mL andexanet vs (2.9) ng/mL placebo
-30.3 (8.1) ng/mL andexanet vs (5.3) ng/mL placebo
*1 patient did not receive full andexanet dose due to administration malfunction
N Engl J Med. 2015;373(25):

24. Study Results – Safety Endpoints
Event
ANNEXA-A (all p < 0.001)
ANNEXA-R (all p < 0.001)
Placebo
Part 1
Part 2
GI disorders
Constipation
Dysgeusia 2
General disorders and administration- site conditions
Feeling hot
Flushing 3 1 4
Immune system disorders
Urticaria
Data shown for all adverse events that occurred more frequently with andexanet and that occurred two or more times. All these events were mild and nonserious.
N Engl J Med. 2015;373(25):

25. Study Results – Safety Endpoints
Transient elevations in D-dimer and prothrombin fragments 1 and 2
Returned to normal within hours
Antibodies to factor X or factor Xa did not develop in any participants
Neutralizing antibodies against andexanet were not detected
Non-neutralizing antibodies against andexanet were detected in 1/44 (2%) placebo vs. 17/101 (17%) andexanet
Appeared within days, generally low titers
N Engl J Med. 2015;373(25):

26. Author’s Conclusions
Andexanet rapidly restored factor Xa activity and thrombin generation and reduced unbound factor Xa inhibitor concentrations in apixaban-treated and rivaroxaban-treated older participants The ability of andexanet to reverse anticoagulation markers in participants undergoing anticoagulation with apixaban, rivaroxaban, edoxaban, or enoxaparin makes it a potential universal antidote for both direct and indirect factor Xa inhibitors.
N Engl J Med. 2015;373(25):

27. Critique Small population of healthy, “older” volunteers
Baseline demographics may not mimic real-life patients
Average age was ~58 years
Anti-factor Xa assay not readily available at most institutions
Multiple questions regarding proper dosing of this agent:
Dosing for edoxaban and enoxaparin?
Dosing for first week and first 21 days during VTE treatment with apixaban (10mg BID) or rivaroxaban (15mg BID)?
Dosing the same if last dose was > 3-4 hours ago?
Unclear how long to continue infusion to achieve hemostasis
Patients with urgent bleeding requiring urgent reversal were excluded (currently being assessed in ANNEXA-4)

28. Delayed Approval
FDA delayed the approval of andexanet alfa, asking for:
Additional information primarily related to manufacturing
Additional data supporting inclusion in the label of two additional anticoagulants (edoxaban and enoxaparin)
Company needs to finalize its review of clinical amendments to Portola’s post-marketing commitments that were recently submitted
CardioBrief. Accessed August 18, 2016.

29. ANNEXA-4
Designed to evaluate andexanet in patients with acute major bleeding that was potentially life-threatening
Predominantly GI and ICH
67 patients for whom data is available (32 rivaroxaban, 31 apixaban, 4 enoxaparin)
37 out of 47 (79%) in efficacy population achieved excellent or good hemostasis
12 out of 67 (18%) in safety population experienced a thromboembolic event

30. References
Apixaban [package insert]. Available at Accessed August 24, 2016
Rivaroxaban [package insert]. Available at Accessed August 24, 2016
Edoxaban [package insert]. Available at Accessed August 24, 2016.
Sabir I, Khavandi K, Brownrigg J, Camm AJ. Oral anticoagulants for Asian patients with atrial fibrillation. Nat Rev Cardiol. 2014;11(5):
Tummala R, Kavtaradze A, Gupta A, Ghosh RK. Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data. Int J Cardiol. 2016;214:292-8.
ANNEXA: Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373(25):
Husten L. “FDA Delays Approval of NOAC Reversal Drug. Agency wants more information.” CardioBrief. Accessed August 18,
Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016;

31. Acknowledgments Journal Club Mentor: Program Director:
Matthew Lillyblad, PharmD, BCPS-AQ Cardiology
Program Director:
Rob DiDomenico, PharmD, FCCP, BCPS-AQ Cardiology
ACCP Cardiology PRN Journal Club Coordinators:
Carrie S. Oliphant, PharmD, FCCP, BCPS-AQ Cardiology
Genevieve Hale, PharmD, BCPS
Zachary Noel, PharmD, BCPS

32. Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors Apixaban (ANNEXA-A) and Rivaroxaban (ANNEXA-R)
Stephanie Dwyer, PharmD
PGY2 Cardiology Pharmacy Resident
University of Illinois College of Pharmacy
Presenter
Matthew Lillyblad, PharmD, BCPS-AQ Cardiology
Clinical Pharmacy Coordinator – Cardiology and Critical Care
Clinical Pharmacy Specialist – Advanced Heart Failure
PGY2 Resident Program Director – Cardiology
Mentor
September 13th 2016

33. Thank you for attending!
If you would like to have your resident present, would like to be a mentor, or have questions or comments please the journal club at or
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Join us later this month on September 28th when Dr. Yang He, PGY-2 in Cardiology at the University of Chicago Medical Center, presents Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest