ACCP Cardiology PRN Journal Club

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• ACCP Cardiology PRN Journal Club

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Announcements

• Thank you attending the ACCP Cardiology PRN
  Journal Club
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  presentation are encouraged though!
• Type questions in the messaging box on the left
  and they will be addressed at the conclusion of
  the presentation

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Dr. Quyen Dau

• Completed Bachelor of Science in both Biology and
  Psychology from Baylor University
• Completed her Doctorate of Pharmacy from Texas
  AM College of Pharmacy
• Completed a PGY1 residency at CHI-St. Lukes
  Health-Baylor St. Lukes Medical Center in
  Houston, TX where she is currently a PGY2
  cardiology resident

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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

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Andexanet Alfa for Acute Major Bleeding
Associated with Factor Xa Inhibitors (ANNEXA-4)
Quyen Dau, PharmD PGY-2 Cardiology Pharmacy
Resident CHI St. Lukes Health-Baylor St. Lukes
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/Cardi
ology University of Colorado Hospital Mentor
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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. 201620273 Pollack
CV, Reilly PA, Eikelbloom J, et al. N Engl J
Med. 2015373511-20
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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.2016129(11S)S80-S8
8.
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ANNEXA-A/R Trial
Siegal D et al. N Engl J Med. 2015 37325
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ANNEXA-A/R Study Treatment
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ANNEXA-A/R Results
Apixaban Apixaban Apixaban Apixaban Rivaroxaban Rivaroxaban Rivaroxaban Rivaroxaban
Part 1 bolus only Part 1 bolus only Part 2 bolusinfusion Part 2 bolusinfusion Part 1 bolus only Part 1 bolus only Part 2 bolusinfusion Part 2 bolusinfusion
Adexanet Placebo Adexanet Placebo Andexanet Placebo Andexanet Placebo
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) lt0.001 lt0.001 lt0.001 lt0.001 lt0.001 lt0.001 lt0.001 lt0.001
There were no serious or severe adverse events,
and no thrombotic events were reported.
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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

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ANNEXA-4

• Andexanet Alfa for Acute Major Bleeding
  Associated with Factor Xa Inhibitors

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ANNEXA-4 Objective

• Evaluate the use of andexanet in patients with
  acute major bleeding that was potentially
  life-threatening

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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

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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 lt7 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
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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

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Dose Selection
If there is a delay between medical
presentation and start of andexanet of more than
7 hours, the patient received the dose for
rivaroxaban gt7 hours ago
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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 1281234-1243
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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
  

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Rating System for Effective Hemostasis Rating System for Effective Hemostasis Rating System for Effective Hemostasis 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 gt1 AND 4 hours after the end of infusion and 2 units plasma, coagulation factor or blood products (excludes pRBCs) Cessation of bleeding gt4 hours after the end of the infusion AND/OR gt2 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 gt20 but 35 increase in hematoma volume compared to baseline on a repeat CT or MRI scan at 12-hour time point gt35 increase in hematoma volume on a CT or MRI compared to baseline on a repeat CT or MRI scan at 12-hour time point
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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

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Statistical Analysis

• Data were reported as means (SD) or medians and
  interquartile ranges for continuous variables and
  frequencies for categorical variables

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ANNEXA-4 Study Design
Safety and Follow up
2-hr IV infusion
IV Bolus
30 days
4 hrs
8 hrs
12 hrs
3 days
Baseline
Bleeding and laboratory assessment
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Baseline Characteristics
Characteristic Efficacy Population (N47) Safety Population (N67)
Age-yr 77.110.1 77.110.0
Male sex-no. () 24 (51) 35 (52)
White race-no. () 36 (77) 54 (81)
Time from presentation until andexanet bolus-hr 4.81.8 4.81.9
Estimated Creatinine Clearance-no. () lt30 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 Atrial fibrillation Heart failure Diabetes mellitus 7 (15) 15 (32) 16 (34) 4 (9) 34 (72) 19 (40) 17 (36) 13 (19) 17 (25) 20 (30) 6 (9) 49 (73) 23 (34) 23 (34)
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Baseline characteristics
Factor Xa Inhibitor Efficacy Population N47 Safety Population N67
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) 12.04.1 297.0171.0 19.3 (12.0-26.9) 32 20 (15-20) 12.84.2 247186.0 16.7 (10.2-25.5)
Apixaban, 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 20 5 (5-10) 11.04.7 174.597.0 10.5 (8.1-19.2) 31 5 (5-10) 12.14.7 137.7102.3 9.4 (6.0-19.2)
Enoxaparin, N Median daily dose (IQR)-mg Time from last dose to andexanet bolus Baseline anti-factor Xa activity-ng/mL 1 200 13.1 0.6 4 90 (80-150) 10.83.5 0.40.2
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Characteristics of Acute Major Bleeding Episodes
Characteristics Efficacy Population N47 Safety Population N67
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) 14.11.7 12/20 (60) 7/20 (35) 1/20 (5) 28 /67 (42) 14.11.7 14/28 (50) 11/28 (39) 3/28 (11)
Other bleeding site Nasal Pericardial, pleural, retroperitoneal Genital or urinary Articular 2/47 (4) 0 1/2 (50) 1/2 (50) 0 6/67 (9) 1/6 (17) 3/6 (50) 1/6 (17) 3/6 (50)
Clinical outcome Death Thromboembolic event 7/47 (15) 7/14 (15) 10/67 (15) 12/67 (18)
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Anti-Factor Xa Activity and Percent Change from
BaselineRivaroxaban
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Anti-Factor Xa Activity and Percent Change from
BaselineApixaban
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Hemostatic Efficacy at 12 hours
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Thromboembolic events or Death During the 30-Day
Study Period
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N67
Death-no. () Cardiovascular causes Non-cardiovascular causes 10 (15) 6 (9) 4 (6)
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Thromboembolic events or Death During the 30-Day
Study Period
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Thromboembolic events or Death During the 30-Day
Study Period
N67
Thromboembolic events-no. () Myocardial infarction Stroke Deep-vein thrombosis Pulmonary Embolism 12 (18) 1 (1.5) 5 (7.5) 7 (10.4) 1 (1.5)
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.

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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.

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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

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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?

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Acknowledgments

• Journal Club Mentor
• 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

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References

• Brown et al. Nonvitamin K antagonist oral
  anticoagulant activity challenges in measurement
  and reversal. Critical Care. 2016 20273
• Pollack CV, Reilly PA, Eikelbloom J, et al.
  Idarucizumab for dabigatran reversal. N Engl J
  Med. 2015373511-20
• Milling TJ, Kaatz S. Preclinical and clinical
  data for factor Xa and universal reversal
  agents. Am J Med.2016129(11S)S80-S88
• Siegal D et al. Andexanet alfa for the reversal
  of factor Xa inhibitor activity. N Engl J Med.
  2015 37325
• 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 1234-1243.
• Connolly S et al. Andexanet alfa for acute major
  bleeding associated with factor Xa inhibitors. N
  Engl J Med. 2016. DOI10.1056/NEJMoa1607887

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Andexanet Alfa for Acute Major Bleeding
Associated with Factor Xa Inhibitors (ANNEXA-4)
Quyen Dau, PharmD PGY-2 Cardiology Pharmacy
Resident CHI St. Lukes Health-Baylor St. Lukes
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/Cardi
ology University of Colorado Hospital Mentor
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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 e-mail the journal club at
  accpcardsprnjournalclub_at_gmail.com or
  carrie.Oliphant_at_mlh.org
• A PB Works Site has been created that houses our
  recorded calls, handouts, and Summary/QA
  documents. The link is
• https//accpcardsprnjournalclub.pbworks.com/
• Join us next month on Wednesday, November 9th as
  Dr. Laura Fuller, from Johns Hopkins, and her
  mentor, Dr. Brent Reed, present the Targeting
  Acute Congestion With Tolvaptan in Congestive
  Heart Failure (TACTICS-HF) trial