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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
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Anticoagulation Therapy in 2019: Exploring Beyond Warfarin
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.
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Elizabeth Pogge, PharmD, MPH, BCPS AQ Cardiology, FASCP
• Professor-Midwestern University in Glendale, AZ
• Ambulatory Care Pharmacist-Cardiac Solutions
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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
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Disclosure – Dr. Pogge and Dr. Sibicky
We have no actual or potential conflicts of interest to disclose.
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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
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Audience Polling
What is your favorite direct oral anticoagulant to recommend for elderly patients (> 65 years of age)?
A. DabigatranB. RivaroxabanC. ApixabanD. Edoxaban
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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)
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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
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Apixaban, dabigatran, rivaroxaban, edoxaban, betrixaban Prescribing Information. 2019.
Summary of DOACs Based on Indication
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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
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Apixaban, dabigatran, rivaroxaban, edoxaban, betrixaban Prescribing Information. 2019.
Summary of DOACs Based on Indication
How are we going to keep all these doses straight?!?!?!
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Assessing Stroke Risk in Atrial FibrillationCHA2DS2-VASc Condition Points
Congestive heart failure or LV dysfunction
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Hypertension; (diagnosis regardless of BP)
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Age ≥ 75 years 2Diabetes mellitus 1Stroke or TIA or thromboembolism 2Vascular disease (Defined as prior MI, PAD, or aortic plaque)
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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
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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
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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.
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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
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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
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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
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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.
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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.
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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.
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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.
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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
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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
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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.
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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.
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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
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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)
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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
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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.
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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.
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Self-Assessment Question
In atrial fibrillation patients who are ≥ 75 years of age, DOACs are more effective than warfarin at preventing strokes/systemic embolism
A. TrueB. False
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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
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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
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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
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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
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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.
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HEMORR2HAGES
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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.
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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?
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Bleeding Severity and Assessment
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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)
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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.
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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
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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)
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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.
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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.
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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
43Pollack CV, et al. N Engl J Med 2015;373:511-20.
Praxbind (idarucizumab) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc., 2018.
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Andexanet Alfa: Mechanism of Action
44Pollack CV, et al. N Engl J Med 2015;373:511-20.
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Andexanent Alfa: Dosing
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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.
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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.
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PCCs for Major Bleeding
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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.
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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.
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Self-Assessment Question
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
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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
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American College of Cardiology
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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
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ACC: Atrial Fibrillation Clinical Toolkit
52“Clinical Toolkit” Available: https://www.acc.org/tools-and-practice-support/clinical-toolkits/atrial-fibrillation-afib
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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
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ACC:DOAC Dosing for Atrial FibrillationInfographic
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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
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Social Media
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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/)
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Practice Guide from the ESC
https://www.escardio.org/Guidelines/Recommended-Reading/Heart-Rhythm/Novel-Oral-Anticoagulants-for-Atrial-Fibrillation
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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.
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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
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