Anticoagulation Therapy in 2019 ea - American Society of ...AF plus 2 or more non gender risk factor ≥ 2 in men ≥ 3 in women Anticoagulation strongly recommended AF plus 1 or more

10/21/19

1

Anticoagulation Therapy in 2019: Exploring Beyond Warfarin

Elizabeth Pogge, PharmD, MPH, BCPS AQ Cardiology, FASCPProfessor, Midwestern University

Stephanie Sibicky, PharmD, MEd, BCGP, BCPSAssistant Clinical Professor, Northeastern University

stephsibicky

1


To enter the Q&A and polling questions for this activity, go to ascp.com/qa and click on the title of this activity, as seen below.

2

10/21/19

2

Elizabeth Pogge, PharmD, MPH, BCPS AQ Cardiology, FASCP

• Professor-Midwestern University in Glendale, AZ

• Ambulatory Care Pharmacist-Cardiac Solutions

3

3

Stephanie Sibicky, PharmD, MEd, BCGP, BCPS

• Assistant Clinical Professor, Northeastern University, Boston, MA

• Inpatient, Internal Medicine Clinical Pharmacy Faculty at Brigham and Women’s Hospital

4

4

10/21/19

3

Disclosure – Dr. Pogge and Dr. Sibicky

We have no actual or potential conflicts of interest to disclose.

5

5

Learning Objectives

At the conclusion of this knowledge-based activity, the participant will be able to:

• Compare and contrast indications for direct oral anticoagulants, emphasizing recent indication expansions

• Discuss the use of direct oral anticoagulants in elderly individuals taking into account co-morbid disease states

• Describe current strategies to prevent and treat bleeding in patients on direct oral anticoagulants

• Identify anticoagulation resources that can be utilized in current practice

6

6

10/21/19

4

Audience Polling

What is your favorite direct oral anticoagulant to recommend for elderly patients (> 65 years of age)?

A. DabigatranB. RivaroxabanC. ApixabanD. Edoxaban

7

7

The History of Direct Oral Anticoagulants (DOACs)

2010 2011 2012 2013 2014 2015 2016 2017 2018

FDA approves first DOAC dabigatran for AF

(2010)

FDA approves rivaroxaban for AF

(2011)

FDA approves apixaban for AF

(2012)

FDA approves edoxaban for AF and VTE

(2015)

FDA approves rivaroxaban for VTE

(2012)

FDA approves dabigatran for VTE

(2014)

FDA approves apixaban for VTE

(2014)

FDA approves idarucizumab

(2015)

FDA approves betrixaban for VTE

(2017)

FDA approves andexanet alfa

(2018)

Abbreviations:AF = atrial fibrillationFDA = food and drug administrationVTE = venous thromboembolismPAD= peripheral artery diseaseCAD= coronary artery diseaseRed agents are reversal agents

Drug approvals and databases. 2019. Available at: https://www.fda.gov/drugs/development-approval-process-drugs/drug-approvals-

and-databases 8

FDA approves rivaroxaban for

PAD/CAD(2018)

8

10/21/19

5

Dabigatran (Pradaxa®) Rivaroxaban (Xarelto®) Apixaban (Eliquis®) Edoxaban (Savaysa®) Betrixaban (Bevyxxa®)

Dose in atrialfibrillation

150 mg twice a day with or without food

20 mg once daily with a large meal

(food ↑ bioavailability)

5 mg twice daily with or without food

60 mg once daily with or without food Not FDA-approved

Dose adjustments in

atrialfibrillation

CrCl 15-30 mL/min*: 75 mg twice daily

CrCl 15-50 mL/min*: 15 mg once daily with

food

Dose reduction of 2.5 mg twice daily if 2 or more of the following

- Age ≥ 80 yrs- Wt ≤ 60 kg

- SCr ≥ 1.5 mg/dL

Not recommended if CrCl > 95 ml/min

CrCl 15 to 50 mL/min*: 30 mg once daily

Not FDA-approved(For VTE prophylaxis: CrCl 15 to 30 mL/min: 80 mg X 1, then 40 mg

daily)

Dose in VTE treatment

150 mg twice daily after 5-10 days of parenteral

anticoagulant

15 mg every 12 hours for 21 days then 20 mg

daily

10 mg twice daily for 7 days then 5 mg twice

daily

60 mg once daily after 5-10 days of parenteral

anticoagulantWt < 60 kg: 30 mg once

daily

Not FDA-approved

Dose in VTE prophylaxis 150 mg twice daily 10 mg daily 2.5 mg twice daily Not FDA approved 160 mg X 1; then 80 mg

daily (see above)Dose in

CAD/PAD Not FDA approved 2.5 mg twice daily Not FDA approved Not FDA approved Not FDA-approved

* Patients with a CrCl < 30 ml/min were excluded from clinical trials

9

Apixaban, dabigatran, rivaroxaban, edoxaban, betrixaban Prescribing Information. 2019.

Summary of DOACs Based on Indication

9

Dabigatran (Pradaxa®) Rivaroxaban (Xarelto®) Apixaban (Eliquis®) Edoxaban (Savaysa®) Betrixaban (Bevyxxa®)

Dose in atrialfibrillation

150 mg twice a day with or without food

20 mg once daily with a large meal

(food ↑ bioavailability)

5 mg twice daily with or without food

60 mg once daily with or without food Not FDA-approved

Dose adjustments in

atrialfibrillation

CrCl 15-30 mL/min*: 75 mg twice daily

CrCl 15-50 mL/min*: 15 mg once daily with

food

Dose reduction of 2.5 mg twice daily if 2 or more of the following

- Age ≥ 80 yrs- Wt ≤ 60 kg

- SCr ≥ 1.5 mg/dL

Not recommended if CrCl > 95 ml/min

CrCl 15 to 50 mL/min*: 30 mg once daily

Not FDA-approved(For VTE prophylaxis: CrCl 15 to 30 mL/min: 80 mg X 1, then 40 mg

daily)

Dose in VTE treatment

150 mg twice daily after 5-10 days of parenteral

anticoagulant

15 mg every 12 hours for 21 days then 20 mg

daily

10 mg twice daily for 7 days then 5 mg twice

daily

60 mg once daily after 5-10 days of parenteral

anticoagulantWt < 60 kg: 30 mg once

daily

Not FDA-approved

Dose in VTE prophylaxis 150 mg twice daily 10 mg daily 2.5 mg twice daily Not FDA approved 160 mg X 1; then 80 mg

daily (see above)Dose in

CAD/PAD Not FDA approved 2.5 mg twice daily Not FDA approved Not FDA approved Not FDA-approved

* Patients with a CrCl < 30 ml/min were excluded from clinical trials

10

Apixaban, dabigatran, rivaroxaban, edoxaban, betrixaban Prescribing Information. 2019.

Summary of DOACs Based on Indication

How are we going to keep all these doses straight?!?!?!

10

10/21/19

6

Assessing Stroke Risk in Atrial FibrillationCHA2DS2-VASc Condition Points

Congestive heart failure or LV dysfunction

1

Hypertension; (diagnosis regardless of BP)

1

Age ≥ 75 years 2Diabetes mellitus 1Stroke or TIA or thromboembolism 2Vascular disease (Defined as prior MI, PAD, or aortic plaque)

1

Age 65-74 years 1Sex Category (female gender) 1

11Lip GY. CHEST. 2018. 154(5):1121-1201.

↑ Score = ↑ Risk

Risk Factors CHA2DS2-VAScScore

Recommended Treatment

AF plus 2 or more non gender risk factor

≥ 2 in men≥ 3 in women

Anticoagulation strongly recommended

AF plus 1 or more non gender risk factor

1 in men2 in women

Anticoagulation is preferred-ASA monotherapy or no antithrombotic therapy may be considered

AF plus 0 non gender risk factors

0 in men1 in women

No antithrombotic therapy preferred

11

What is NEW with DOACs?

• Expanded indications• Low dose DOACs for extended VTE treatment• Chronic stable coronary artery disease/peripheral artery disease (CAD/PAD)

• Special populations• Cancer• Renal dysfunction

12

12

10/21/19

7

DOACs in Extended VTE Treatment

• Extended VTE treatment = ~3 months to indefinite• Patient population of interest is unprovoked FIRST VTE

• CHEST 2016 guidelines recommend long term anticoagulation in those with low-moderate risk of bleeding

• Older adults may have a high risk of bleeding which would favor no extended anticoagulation therapy

• Traditionally, anticoagulation is continued at the treatment dose

13Castellucci LA. Res Pract Thromb Haemost. 2018;2:529-534.

Kearon C, et al. CHEST. 2016; 149(2):315-352.

13

DOACs in Extended VTE Treatment

• Apixaban and rivaroxaban have been studied at a lower doses

• Limitations• Recurrent VTE and bleeding rates were low • Average age ~56-59 years

14Castellucci LA. Res Pract Thromb Haemost. 2018;2:529-534.

Study Comparator 1 Comparator 2 ResultsEINSTEIN-CHOICE Rivaroxaban 10 mg daily* Aspirin 100 mg daily Lower rates of recurrent

nonfatal or fatal VTE with no difference in bleeding ratesAMPLIFY-EXT Apixaban 2.5 mg twice daily* Placebo

*Application: Rivaroxaban 10 mg daily and apixaban 2.5 mg twice daily are FDA approved for extendedVTE treatment after at least 6 months of therapeutic anticoagulation

14

10/21/19

8

Rivaroxaban in Chronic CAD/PAD

• Rivaroxaban + aspirin is approved to reduce the risk of major cardiovascular events in chronic CAD/PAD based on results of the COMPASS trial• Rivaroxaban 2.5 mg twice daily + aspirin 100 mg daily vs aspirin 100 mg daily

for 23 months• Lower rate of the primary outcome of CV death, stroke, or nonfatal myocardial

infarction in the rivaroxaban group: NNT = 76• Lower rate of all cause mortality: NNT = 143• Bleeding was higher in the rivaroxaban group: NNH = 83

• Mainly gastrointestinal bleeding

What about our geriatric patients who are at a higher risk of bleeding??

15COMPASS Trial. N Engl J Med. 2017;377:1319-30.

Abbreviations:NNT= number needed to treatNNH= number needed to harm

15

Rivaroxaban in CAD/PAD: Geriatric Subgroup

16Kerkar et al. Indian Heart J. 2018;70:911-14.

Age Number of patients NNT NNH< 65 years 4334 48 500> 65 years 13,944 91 63

Application: Of those > 65 years, 91 patients would need to be treated for 23 months with rivaroxaban + ASA instead of ASA alone to prevent 1 CV death, stroke, or nonfatal MI while

only 63 patients would need to be treated for 23 months for 1 patient to experience a bleeding event

Risk >>> Benefit

16

10/21/19

9

DOACs in Cancer-associated Thrombosis (CAT)

17Rojas-Hernadez CM, et al. Drugs. 2019;79(6):621-631.

CAT Prophylaxis in High Risk Patients(Khorana score ≥ 2)

Follow-up: 6 months

CAT TreatmentAll agents were given at the current FDA-approved VTE

treatment doseAverage follow-up: 6 months

CASSINI: Rivaroxaban 10 mg daily vs. placeboResults: No difference in VTE rates and similar major bleeding rates

Select-D: Rivaroxaban vs dalteparinResults: ↓ rate of VTE, similar major bleeding rates, ↑ rates of non-major bleeding

ADAM VTE: Apixaban vs dalteparinResults: ↓ rate of VTE and similar major bleeding rates

AVERT: Apixaban 2.5 mg twice daily vs. placeboResults: ↓ rate of VTE and similar major bleeding rates

HOKUSAI CANCER: Edoxaban vs dalteparinResults: No difference in VTE rates,↑ major bleeding with edoxaban, similar rates of non-major bleeding

Bottom Line: Rivaroxaban, apixaban, or LMWH may be considered for VTE prophylaxis in high risk patients.LMWH is the standard of care for CAT. Edoxaban, rivaroxaban, and apixaban may be considered as

alternatives; they may increase bleeding risk, particularly in GI cancers.

17

DOACs in Renal Dysfunction

• Patients with atrial fibrillation and renal dysfunction are at a increased risk of systemic embolic events and bleeding relative to those without chronic kidney disease• Stroke risk increases 7% with every 10 mL/min/1.73 m2 decrease in eGFR

• Cockcroft-Gault was used to estimate creatinine clearance in all phase III clinical trials of DOAC• Utilized ACTUAL body weight

18Fanikos et al. The American Journal of Medicine. 2017;130: 1015-1023.

18

10/21/19

10

End Stage Renal Disease on Hemodialysis (HD)

• Initially pharmacokinetic data showed apixaban may be a safe alternative to warfarin• Most recently, a retrospective cohort study came to the following

conclusions (for patients with atrial fibrillation):• Apixaban 5 mg twice daily as compared to warfarin was associated with a lower

incidence of stroke/SE, major bleeding, and death• Apixaban 2.5 mg twice daily as compared to warfarin was associated with a lower

incidence of major bleeding but no difference in the rates of stroke/SE or deathBottom line: Apixaban 2.5 mg twice daily should only be used in HD

patients with atrial fibrillation if they are ≥ 80 years or weigh ≤ 60 kg

19Siontis et al. Circulation. 2018;138(15):1519-29.

19

Poll: To access the polling questions, go to this link: ascp.com/qa and select the “Anticoagulation Therapy in 2019: Exploring Beyond Warfarin” activity, as seen below.

20

10/21/19

11

Self-Assessment Question

Which of the following agents would be best to recommend for cancer associated thromboprophylaxis?

A. Rivaroxaban 15 mg twice daily for 21 days then 20 mg once dailyB. Edoxaban 60 mg dailyC. Dabigatran 150 mg twice dailyD. Apixaban 2.5 mg twice daily

21

21

Learning Objectives






22

22

10/21/19

12

DOACs in the Elderly

• Elderly individuals are often underrepresented in clinical trials• Bleeding risk is higher in elderly adults• American Geriatrics Society/Beers Criteria 2019

• Dabigatran and rivaroxaban are listed in the 2019 AGS/Beers Criteria to be used cautiously in those 75 years of age and older

• Dabigatran has a lack of safety data in those with CrCl < 30 mL/min

23AGS. J Am Geriatr Soc. 2019;67:674-694.

23

DOACs for AF in the Elderly

• Among adults ≥ 75 years of age, randomized controlled trials have demonstrated that DOACs have a lower frequency of stroke/systemic embolism and a noninferior risk of major bleeding when compared to warfarin• Improved efficacy• Equivalent safety

• A recent retrospective observational study confirmed these findings in adults ≥ 80 years and observed that each agent may differ in their major bleeding rates

24Kim et al. J Cardiol. 2018;72(2):105-112.

Deitelzweig S, et al. J Am Geriatr Soc. 2019;67:1662-71.

24

10/21/19

13

DOAC vs Warfarin in AF

Key Points• All DOAC offer

improved efficacy• Apixaban was superior

in all categories• Major bleeding was

similar with dabigatran• Major bleeding was ↑

with rivaroxaban

Deitelzweig S, et al. J Am Geriatr Soc. 2019;67:1662-71 25

25

DOACs for VTE in the ElderlyResults from VTE randomized controlled trial have shown that DOACs as compared to warfarin in those ≥ 75 years provide at least equal efficacy (possibly improved) as well as ↓ rates of major bleeding

Van ES N, et al. Blood. 2014;124(12):1968-78. 26

Recurrent VTE and major bleeding associated with DOACs compared to warfarin by patient age (pooled RR with 95% CI)

DOACs vs warfarinRecurrent VTE or VTE-related death

DOACs vs warfarinMajor bleeding

Age ≥ 75 years 0.56 (0.38-0.82) 0.49 (0.25-0.96)

Age < 75 years 0.99 (0.85-1.17) 0.62 (0.45-0.84)

26

10/21/19

14

Inappropriate Dosing in the Elderly

• Overdosing and underdosing are common in elderly patients• Underdosing has been seen more commonly in older adults (studies

have shown up to 30%!)• Underdosing may be more common with apixaban• Remember: only reduce the dose if patients have atrial fibrillation and meet

2 of the 3 criteria (age ≥ 80 years, weight ≤ 60 kg, SCr ≥ 1.5 mg/dL)

• For dabigatran and rivaroxaban, dose reduction should only be done if CrCl < 30 mL/min (dabigatran) or 15-50 mL/min (rivaroxaban)

Lavoie et al. J Atr Firbillation 2016;9:1478.Moudallel et al. Pharmacol 2018;9:1220.

Pogge, et al. Senior Care Pharmacist. 2019;[ePub ahead of print]. 27

27

DOAC Counseling Points

• Dabigatran is a prodrug given in an acidic core• Increased risk of GI upset• Must store in original container – NOT in pill boxes• Swallow whole, do not crush

• Rivaroxaban should be given with the largest meal of the day• This may NOT be the evening meal for all of our patients• Real world data suggests rivaroxaban is associated with a higher rate of GI

bleeding

• Apixaban and rivaroxaban may be crushed for administration

28Steffel et al. Eur Heart J. 2018;39(16):1330-1393.

28

10/21/19

15


29


In atrial fibrillation patients who are ≥ 75 years of age, DOACs are more effective than warfarin at preventing strokes/systemic embolism

A. TrueB. False

30

30

10/21/19

16

Learning Objectives






31

31

Bleeding and Risk Factors

32Decousus H, et al. Chest. 2011;139:69.

Schünemann HJ, et al. Blood Adv. 2018; 2:3198.

NON-MODIFIABLE RISK FACTORS MODIFIABLE RISK FACTORS

• Age (linear increase over age 60)• Sex (male, OR = 1.5)• Race (African decent, OR = 4)• Renal or hepatic insufficiency (eGFR < 30,

OR = 2), • History of prior bleed

• Alcohol use• Anemia• Chronic steroid or NSAID therapy• Low body weight• Uncontrolled comorbidities (e.g., peptic

ulcer disease, diabetes)

OR = odds ratio; eGFR – estimate glomerular filtration rate, NSAID = nonsteroidal anti-inflammatory drug

32

10/21/19

17

Clinical Characteristics Points

Hypertension 1

Abnormal renal function (on dialysis, transplant, SCr > 2.6) 1

Abnormal liver function (cirrhosis, bilirubin > 2X ULN, AST/ALT/ALP > 3X ULN)

1

Stroke 1

Bleeding 1

Labile INRs (unstable/high INRs, < 60% time in therapeutic range) 1

Elderly (> 65 years old) 1

Drugs (aspirin or NSAIDs) --OR-- alcohol use 1 or 2

Maximum Score = 9

HAS-BLED Bleeding Risk Score

33

HAS-BLED Score

Bleeds per 100 patient

years

0 1.13

1 1.02

2 1.88

3 3.74

4 8.7

5-9 No data

Pisters R, et al. Chest. 2010;138(5):1093.Lip GY. Am J Med. 2011 Feb;124(2):111-4.

Abbreviations:Scr = serum creatinine, ULN = upper limit of normal, AST = aspartate amino-transferase, ALT = alanine amino-transferase, ALP = alkaline phosphatase, INR = international normalized ratio, NSAIDs = non-steroidal anti-inflammatory drugs

33

34

ATRIA• 3 points each: anemia,

severe renal disease (eGFR < 30 or HD)

• 2 points: age ≥ 75• 1 point each: any prior

hemorrhage, diagnosed hypertension

Rate of Bleeding (Points)

Event Rate per 100 Patient

Years

Low (0-3) 0.76

Intermediate (4) 2.62

High (5-10) 5.76

ORBIT• 1 point each: age ≥ 75,

insufficient kidney function (eGFR < 60), treatment with an antiplatelet

• 2 points each: reduced Hgb or Hct or history of anemia, bleeding history

Rate of Bleeding (Points)

Event Rate per 100 Patient

Years

Low (0-2) 2.4

Intermediate (3) 4.7

High (4-7) 8.1Abbreviations:ATRIA = Anticoagulation and Risk Factors in Atrial Fibrillation; ORBIT = Outcomes Registry for Better Informed Treatment of Atrial Fibrillation; eGFR = estimated glomerular filtration rate; Hgb = hemoglobin; Hct = hematocrit

Fang MC, et al. J Am Coll Cardiol. 2011;58(4):395.O’Brien EC, et al. Eur Heart J. 2015;36:3258-3264.

34

10/21/19

18

HEMORR2HAGES

35

Points Risk of Major Bleed per 100 patient Years

0 1.9

1 2.5

2 5.3

3 8.4

4 10.4

≥ 5 12.3

Clinical Characteristics PointsHepatic or renal disease 1

Ethanol use disorder 1

Malignancy 1

Older age (> 75 years) 1

Reduced platelet count/function (includes aspirin therapy) 1

Re-bleeding risk (history of prior bleed) 2

Hypertension 1

Anemia 1

Genetic factors 1

Excessive fall risk 1

Stroke 1

Gage BF, et al. Am Heart J. 2006;151(3):713.

35

36Steffel J, et al. Eur Heart J. 2018 Apr 21;39(16):1330-1393.

Risk Reduction Strategies and Checklist

Interval Comments

Adherence Each visit Bring medications/list, counsel/educate about importance of adherence, recommend adherence aides if necessary, consider insurance coverage

Thromboembolism Each visit Has the patient had any changes to their condition (e.g., TIA, stroke)?

Bleeding Each visit Any evidence of bleeding? Does the patient know what to look for? Reinforce education and make adjustments as necessary

Side effects Each visit In relation to the anticoagulant, do changes need to be made?

Drug interactions Each visit Include prescription and over-the-counter medications

Blood sampling 6-months/ yearly

Renal and hepatic function, hemoglobin/hematocrit, platelets(if ≥ 75 years old, every 6 months)

X-monthly If CrCl ≤ 60 ml/min, recheck at interval = CrCl/10

Manage modifiable risk factors for bleeding

Each visit Based on current guidelines, control hypertension, reduce medications that can increase risk, alcohol

Reassess if anticoagulant is appropriate

Each visit Is this the best choice for the patient?Is the dose correct?

36

10/21/19

19

Bleeding Severity and Assessment

37

Amount or severity of bleed? Last dose of medication?

Location? Intentional or unintentional overdose?

Actively bleeding? History of renal or hepatic dysfunction?

Medications? (including anticoagulant, antiplatelets)

Comorbidities?(e.g., thrombocytopenia)

Life-threatening or imminently fatal bleeding

(e.g., massive GI bleed, intracranial, retroperitoneal)

Minor bleeding(e.g., slow GI bleed, soft-tissue

bleeding, epistaxis)

37

Consider DOAC PropertiesHalf-life

(Normal Renal/Hepatic Function)

Five Half-lives Renal/Hepatic Excretion

Dabigatran 12-17 hours 2.5-3.5 days 80-85% renal

Rivaroxaban 5-9 hours 1-2 days 35% renal; accumulation possible in severe hepatic impairment

Apixaban 8-15 hours 1.5-3 days 25% renal; accumulation possible in severe hepatic impairment

Edoxaban 6-11 hours 1.5-2 days 35% renal; accumulation possible in severe hepatic impairment

Betrixaban 19-27 hours 4-5.5 days 11% renal; not recommended in hepatic impairment

38Scaglione F. Clin Pharmacokinet. 2013;52(2):69.

38

10/21/19

20

Strategies for Minor Bleeding

• Observation• Local measures (e.g., pressure)• Anticoagulant discontinuation or interruption• Potential antifibrinolytic agents (e.g., tranexamic acid, epsilon-

aminocaproic acid)• Data is limited on use for DOAC-associated bleeding• Utility if other agents cannot be used due to bleeding risk or comorbidities• Usually available in an acute care setting, low cost, low risk of thrombosis

39

39

Available Strategies for Major Bleeding with DOACs• Antidotes:

• Idarucizumab for dabigatran• Andexanet alfa for factor Xa inhibitors

• Prothrombin complex concentrate (PCC)• Antifibrinolytics• Oral activated charcoal (if last dose ingested in previous 3 hours)• There is a lack of data for use of fresh frozen plasma (FFP),

desmopressin (DDAVP), or recombinant activated factor VII (rFVIIa)

40

40

10/21/19

21

Idarucizumab: Mechanism of Action

41Balla S, et al. Postgrad Med J. 2017 Apr;93(1098):221-225.

Eikelboom J, et al. Circulation. 2015 Dec 22;132(25):2412-22.

41

Idarucizumab: Dosing

• Dose:• 5 grams total: 2 x 2.5 gram IV infuse over 5-10 minutes no more than 15

minutes apart• If aPTT elevated or clinically relevant bleeding persists, can give additional 5 g

dose

• Adverse effects: injection site reaction, headache, constipation, nausea• Cost: ∼$4,452 (2 x 2.5 g/50 mL vials)

42Pollack CV, et al. N Engl J Med 2015;373:511-20.

Praxbind (idarucizumab) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc., 2018.

42

10/21/19

22

Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD)• Included patients who were older, median age 78 years (range 48-93)• Separated into two groups: A (uncontrolled bleeding), B (undergoing

surgical procedure)• 100% reversal of anticoagulation based on ecarin clotting time and

dilute thrombin time• Thrombotic events occurred in 6.3% in Group A and 7.4% in Group B• Mortality rate was 18.8% in Group A and 18.9% in Group B


Praxbind (idarucizumab) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc., 2018.

43

Andexanet Alfa: Mechanism of Action


44

10/21/19

23

Andexanent Alfa: Dosing

45

Factor Xainhibitor

Factor Xa inhibitor last dose

Timing of Last Dose of Factor Xainhibitor

< 8 hours or unknown > 8 hours

Apixaban≤ 5 mg Low dose

Low dose> 5mg or unknown High dose

Rivaroxaban≤ 10 mg Low dose

> 10 mg or unknown High dose

Cost 100 mg ($3,300)200 mg ($6,600)

Low dose:880 mg ($29,040)

High Dose:1,760 mg ($58,080)

Low dose: 400 mg IV bolus (30 mg/minute), followed within 2

minutes by IV infusion of

4 mg/min for up to 120 minutes

High dose: 800 mg IV bolus (30 mg/minute), followed within 2

minutes by IV infusion of

8 mg/min for up to 120 minutes

Pollack CV, et al. N Engl J Med 2015;373:511-20.Andexxa (andexanet alfa) [package insert]. San Francisco, CA: Portola Pharmaceuticals, Inc., 2018.

45

Andexanet Alfa – A Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA)

ANNEXA A and ANNEXA R• Dose-ranging trials in healthy, older volunteers (median age 57.9 years)• Anti-factor Xa activity reduced > 90% for both apixaban and rivaroxaban• No adverse events, thrombosis, or immune response noted

ANNEXA 4• Multi-center, prospective, open-label, single group trial• Patients with acute bleeding (mean age 77 years)• Anti-factor Xa activity reduced and 79% of patients achieved excellent or good

hemostasis• Safety population (n=67): mortality 15%, thrombosis 18% (30% occurred within 3 days)

46Siegal DM, et al. N Engl J Med 2015;373:2413-24.

Connolly SJ, et al. N Engl J Med 2019;380:1326-35.

46

10/21/19

24

PCCs for Major Bleeding

47

Activated prothrombin complex concentrate (aPCC)

• 4-factor (II, VII, IX, X – factor eight inhibitor bypassing activity, FEIBA®)

• Factor VII is mostly activated• Can be used for dabigatran reversal if

idarucizumab unavailable• Can be used for factor Xa reversal as

alternative

Unactivated prothrombin complex concentrate (PCC)

• 3-factor (II, IX, X – Profilnine®)• 4-factor (II, VII, IX, X inactive forms –

Kcentra®)• 4F-PCC preferred for factor Xa inhibitor

reversal if andexanet unavailable• Limited data comparing to andexanet• Can be used for dabigatran reversal if

idarucizumab unavailable

Shaw JR, et al. Res Pract Thromb Haemost. 2018;2:251–265.

47


48

10/21/19

25


Which of the following antidotes is preferred for reversing the effects of dabigatran?

A. Andexanet alfaB. Unactivated 4-factor PCC (Kcentra®)C. Fresh frozen plasma (FPP)D. Idarucizumab

49

49

Learning Objectives






50

50

10/21/19

26

American College of Cardiology

51

Clinical Toolkits

Atrial fibrillationhttps://www.acc.org/tools-and-practice-support/clinical-toolkits/atrial-fibrillation-afib

Expert Consensus Decision PathwaysBleed Management in Anticoagulationhttp://www.onlinejacc.org/content/early/2017/11/10/j.jacc.2017.09.1085?_ga=2.46614759.1124719807.1566231834-1429624554.1562025473

Infographics

DOAC Dosing for Atrial Fibrillation (AFib)https://www.acc.org/tools-and-practice-support/infographics

Mobile Applications

AnticoagEvaluatorManageAnticoaghttps://www.acc.org/tools-and-practice-support/mobile-resources

“Tools and Practice Support” Avalilable: https://www.acc.org/tools-and-practice-support

51

ACC: Atrial Fibrillation Clinical Toolkit

52“Clinical Toolkit” Available: https://www.acc.org/tools-and-practice-support/clinical-toolkits/atrial-fibrillation-afib

52

https://www.acc.org/tools-and-practice-support/clinical-toolkits/atrial-fibrillation-afib

http://www.onlinejacc.org/content/early/2017/11/10/j.jacc.2017.09.1085?_ga=2.46614759.1124719807.1566231834-1429624554.1562025473

https://www.acc.org/tools-and-practice-support/infographics

https://www.acc.org/tools-and-practice-support/mobile-resources

https://www.acc.org/tools-and-practice-support

10/21/19

27

ACC: Bleed Management in AnticoagulationExpert Consensus Decision Pathway

53“Decision Pathway” Available: http://www.onlinejacc.org/content/early/2017/11/10/j.jacc.2017.09.

1085?_ga=2.46614759.1124719807.1566231834-1429624554.1562025473

53

ACC:DOAC Dosing for Atrial FibrillationInfographic

54

54



10/21/19

28

ACC: Mobile Applications

AnticoagEvaluator• CHA2DS2-VASc calculator• HAS-BLED assessment

• Cockroft-Gault calculator

ManageAnticoag• Periprocedural management of

anticoagulation including interruption and bridging• Addressing and acute bleed• How to reinitiate

anticoagulation

55

55

Social Media

56

Twitter Follow journals like @JACCJournals, @RTPHjournal, @JAMACardioAcademic groups like @ATRIUMRx, @iPharmacistACT, @AnticoagForum

Podcasts Journal findings: JACC Podcast, The European Heart Journal PodcastReviews and News: This Week in Cardiology, Medscape Cardiology Podcast

Videos Feedspot Top 25 Cardiology YouTube Channels (https://blog.feedspot.com/cardiology_youtube_channels/)

56

https://blog.feedspot.com/cardiology_youtube_channels/

10/21/19

29

Practice Guide from the ESC

https://www.escardio.org/Guidelines/Recommended-Reading/Heart-Rhythm/Novel-Oral-Anticoagulants-for-Atrial-Fibrillation

57

57

To access Q&A, go to this link: ascp.cnf.io and select the “Anticoagulation Therapy in 2019: Exploring Beyond

Warfarin” activity, as seen below.

58

https://www.escardio.org/Guidelines/Recommended-Reading/Heart-Rhythm/Novel-Oral-Anticoagulants-for-Atrial-Fibrillation

10/21/19

30


Elizabeth Pogge, PharmD, MPH, BCPS AQ Cardiology, FASCPProfessor, Midwestern University

Stephanie Sibicky, PharmD, MEd, BCGP, BCPSAssistant Clinical Professor, Northeastern University

stephsibicky

59

Documents

Anticoagulation Therapy in 2019 ea - American Society of ...AF plus 2 or more non gender risk factor ≥ 2 in men ≥ 3 in women Anticoagulation strongly recommended AF plus 1 or more