practical management of anticoagulation · practical management of anticoagulation juliann horne,...

PRACTICAL MANAGEMENT OF ANTICOAGULATION

Juliann Horne, PharmD

PGY2 Pharmacy Resident in Ambulatory Care

UNM College of Pharmacy

[email protected]

“THE BLOOD THINS AND THE PLOT THICKENS…”

Disclosure

• No conflicts of interest to disclose

• Thanks to Allison Burnett, PharmD, CACP, PhC and the UNMH Inpatient Anticoagulation Service for much of the material and resources in this presentation.

Learning Objectives

• Compare and contrast available parental anticoagulants.

• Compare and contrast available oral anticoagulants.

• Design an appropriate anticoagulant bridging plan.

• Describe payment challenges and offer solutions for direct oral anticoagulants.

• Given an individual patient, recommend an appropriate anticoagulant therapy.

Outline

Review of coagulation cascade

Review of parenteral anticoagulants

Review of oral anticoagulants

Direct oral anticoagulants (DOACs)

Bridging and switching between agents

Coagulation Cascade

TF/VIIa

Xa

IIa

II

Fibrinogen Fibrin

X IX

IXa VIIIa

Dabigatran

Apixaban Edoxaban Rivaroxaban

Initiation

Amplification

Propagation

Adapted from Weitz JI, Bates SM. J Thromb Haemost 2005; 3: 1843-53.

Fondaparinux

Heparin LMWH

AT

AT

AT

Warfarin

Va

VitK

VitK

VitK

VitK

Ppx = DVT prophylaxis

Agent Heparin LMWH Fondaparinux DTIs

Target Xa/IIa Xa>IIa Xa IIa

Routes IV/SQ IV/SQ IV/SQ IV

Peak effect 1.5-3 h 3-4 h 1-3 h 1-2 h

Half-life 1 h 4 h 17 h 0.5 h

Renal elim. No Yes Yes Some

Reversal with protamine

Complete Partial None None

Lab measure aPTT, anti-Xa Anti-Xa Anti-Xa aPTT

When to avoid

HIT CrCl < 30 HIT

CrCl < 50 Ppx if < 50 kg

High bleed risk

Parenteral Anticoagulants

Monitoring LMWH

• Consider monitoring anti-Xa levels:

• Weight under 50 kg or BMI over 40

• CrCl 30-50 ml/min

• Pregnant women

• No better alternative anticoagulant

• Draw level 4 hours after dose (peak effect)

• After at least 2-3 doses to achieve steady state

UNMH Adult Parenteral Anticoagulant Dosing Guideline.

Caution: Not correlated with

outcomes!

Dosing Target Anti-Xa (IU/mL)

1 mg/kg BID 0.5-1

1.5 mg/kg QD 1-2

1 mg/kg QD renal dosing 0.5-1.5

Agent Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban

Target IIa, VIIa, IXa, Xa

IIa Xa Xa Xa

Peak effect 4-5 days 1.5-3 h 2-4 h 1-3 h 1-2 h

Half-life 40 h 12-17 h 5-9 h 9-14 h 9-11 h

Renal elim. None 80% 33% 25% 35-50%

Dialyzable No Yes No No No

Interactions Many P-gp 3A4, P-gp 3A4, P-gp P-gp

Monitoring Yes No No No No

Antidote Vitamin K No No No No

P-gp = P-glycoprotein 3A4 = Cytochrome P450 3A4 Cove CL, Hylek EM. J Am Heart Assoc. 2013;2:e000136.

Oral Anticoagulants

Outline






DOACs

Approved indications & dosing

Efficacy & safety in NVAF & VTE

Lab measurement

Patient selection

Payment challenges and solutions

DOACs: FDA-Approved Indications

VTE Prophylaxis VTE Treatment Non-valvular AF

Dabigatran (Pradaxa)

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Edoxaban (Savaysa)

• Dabigatran is approved for VTEP in EU and Canada

• Edoxaban is approved for VTEP in Japan

• Rivaroxaban is approved for use in ACS in the EU

0 to 7 days |

Warfarin

UFH LMWH Fondaparinux

Initial treatment

Long term-treatment

Extended treatment

Warfarin

Dabigatran, Edoxaban

Rivaroxaban, Apixaban

3 to 6 months | 1 year to indefinite

DOACs: Changing the Treatment of VTE

Chest. 2012;141(2Suppl):7S-47S.

DOAC: Dosing

• Varies by:

–DOAC

–Indication

–Country

• May require adjustment for:

–Renal impairment

–Age

–Weight

–Drug interactions

–A combination of the above

DOACs: Dosing (FDA Labeling)

Apixaban Dabigatran Rivaroxaban Edoxaban

Non-valvular atrial fibrillation

5 mg PO BID 2.5 mg PO BID*

150 mg PO BID 75 mg PO BID* Avoid: CrCl < 15

20 mg PO daily 15 mg PO daily* Avoid: CrCl < 15

60 mg PO daily 30 mg PO daily* Avoid: CrCl > 95

VTE prophylaxis (orthopedic)

2.5 mg PO BID

Not approved in US

10 mg PO daily Avoid: CrCl < 30

Not approved in US

VTE tx & prevention of recurrence

10 mg PO BID x 7 days, then 5 mg BID 2.5 mg BID after 6 months

150 mg PO BID after parenteral Avoid: CrCl < 30

15 mg PO BID x 21 days, then 20 mg PO daily Avoid: CrCl < 30

60 mg PO daily 30 mg PO daily* after parenteral Avoid: CrCl < 15

* Adjusted for renal impairment, drug interactions, age, low weight or a combination of these factors Treatment doses of rivaroxaban should be taken with largest meal of the day

DOACs



Lab measurement

Patient selection


NON-VALVULAR ATRIAL FIBRILLATION (NVAF)

Meta-Analysis: Efficacy & Safety of DOACs in NVAF

Lancet. 2014;383:955–62.

VENOUS THROMBOEMBOLISM (VTE) TREATMENT

Meta-Analysis: Efficacy in VTE

Prevention of Recurrent VTE

DVT

PE

Non-Fatal PE

Eur J Vasc Endovasc Surg. 2014;48(5):565-75. NOAC | VKA

Meta-Analysis: Safety in VTE

Major Bleeding

Fatal Bleeding

All-Cause Mortality

Net Clinical Benefit

Eur J Vasc Endovasc Surg. 2014;48(5):565-75. NOAC | VKA

DOACs



Lab measurement

Patient selection


Measurement of DOACs

• Increased specificity for target inhibition

• Predictable pharmacokinetics and pharmacodynamics

• Minimal dietary effect

• Less intrasubject and intersubject variability

• Wide therapeutic index

• Do not require routine monitoring

• Dose is not adjusted based on laboratory measurements

• No quantitative “therapeutic ranges” established

Potential indications for DOAC measurement Detection of clinically

relevant levels Detection of expected

on-therapy levels Detection of excessive

levels

• Urgent or emergent invasive procedure

• Neuraxial anesthesia

• Major trauma

• Potential thrombolysis in acute thromboembolism

• Assessing adherence

• Breakthrough thrombosis

• Hemorrhagic episode

• Overdose

• Accumulation? - Renal

insufficiency - Hepatic

impairment - Drug interactions - Elderly

Cuker A, et al. J Am Coll Card. 2014; 64(11): 1128-39

J Am Coll Cardiol. 2014;64:1128-39.

Mea

sure

men

t o

f DO

AC

s

Measurement of DOACs

• Routine coagulation assays

–aPTT, PT, anti-Xa

–Helpful in determining presence of drug (qualitative only)

–Readily available in most reference labs

• Specialty coagulation assays

–Calibrated anti-Xa, TT, dTT, ECT, drug concentration

–Not readily available nor standardized

–Research or investigational use only at this point

J Am Coll Cardiol. 2014;64:1128-39.

Do not use warfarin-based

INR

DOACs



Lab measurement

Patient selection


• Which of the following patients would be considered a good candidate for DOAC therapy?

A. 68 year-old obese male on aspirin and clopidogrel for a drug-eluting stent placed 1 month ago

B. 65 year-old female with diabetes & hypertension, both well-controlled on medication, normal kidney function and new onset atrial fibrillation

C. 37 year-old female with end-stage renal disease, on hemodialysis, who has thrombosed her dialysis fistula

D. 54-year-old male with a history of recurrent VTE and labile INR due to non-compliance with warfarin therapy

Patient Case

Preference for Warfarin:

Patient has ≥ 1 of the following:

Non-adherence to current medications

Mechanical cardiac valve

Requires dual antiplatelets (e.g., ASA, clopidogrel)

Severe renal dysfunction (Estimated CRCl <30 ml/min)

Severe liver dysfunction

Patient’s weight is ≤50 kg or ≥120 kg

Major drug-drug interactions with DOAC (CYP 3A4, P-gp)

Able to comply with warfarin monitoring (no physical,

geographic barriers) and no preference for DOAC

Good TTR (≥65%) with warfarin compliance

Financial barriers to ongoing DOAC access

Preference for LMWH

Patient has ≥ 1 of the following:

Active cancer

Pregnant

DOAC Selection

Patient characteristic Preferred Agent

History of GI bleed Apixaban

Edoxaban (dose adjust)

Prefer once a day dosing Rivaroxaban

Edoxaban

Moderate renal

insufficiency (CrCl 30-49) Apixaban

Rivaroxaban

History of MI Apixaban

Rivaroxaban

History of stroke Apixaban

Dyspepsia Rivaroxaban/apixaban/edoxaban

• Which of the following patients would be considered a good candidate for DOAC therapy?

A. 68 year-old obese male on aspirin and clopidogrel for a drug-eluting stent placed 1 month ago

B. 65 year-old female with diabetes & hypertension, both well-controlled on medication, normal kidney function and new onset atrial fibrillation

C. 37 year-old female with end-stage renal disease, on hemodialysis, who has thrombosed her dialysis fistula

D. 54-year-old male with a history of recurrent VTE and labile INR due to non-compliance with warfarin therapy

Patient Case

DOACs



Lab measurement

Patient selection


Insurance Coverage



Apixaban (Eliquis)

Edoxaban (Savaysa)

NM Medicaid −−

BCBS Molina (PA)

Pres (10 mg only) UHC (PA)

Pres (PA) UHC (PA)

−−

Medicare Part D

US: 100% (87%)

NM: 78% (59%) US: 93% TBD

Commercial US: 96% (80%) NM: 85% (61%) US: 87% (73%) TBD

(% available at lowest branded copay in parentheses)

Patient Assistance Programs



Apixaban (Eliquis)

Edoxaban (Savaysa)

NM Medicaid N/A N/A N/A N/A

Medicare Part D Free 30-day supply card

Free 30-day supply card

Free 30-day supply card

N/A

Commercial $10 copay card

Free 30-day + $5 copay card for 15 mg and

20 mg

Free 30-day + $10 copay card

$4 copay card

Non-insured BIpatient

assistance.com

JJpaf.org: free for those who qualify

(income)

BMSpaf.org: free for those who qualify

(income)

?

DOACs: Advantages

• Improved pharmacokinetic/pharmacodynamic profile

– Rapid onset/offset of action

– Fewer dietary and drug interactions

– Wide therapeutic window allows fixed dosing

– No need for routine monitoring

• Greater convenience and patient satisfaction

• Improved safety profile compared to warfarin

• 20-40% relative risk reduction in major bleeding

• 40-50% relative risk reduction in fatal bleeding

• 60-70% relative risk reduction in intracranial hemorrhage

• Potentially more cost-effective Chai-Adisaksopha, et al. Blood 2014; 124(15):2450-58

Bauer KA. ASH Education Book 2013; 1:464-470 Ruff CT, et al. Lancet 2013; 383 (9921): 955-62

Van Der Hulle T, et al. J Thromb Haemost 2014; 12: 320–8.

DOACs: Disadvantages

• Dose reduction or avoidance in kidney impairment

• Lack of flexibility in dosing

• Limited availability of lab assays to measure anticoagulant effect

• Short half-life mandates strict adherence

• Lack of antidote

• Higher drug acquisition costs and prior authorizations

• Fewer studied/approved indications (e.g. valves, cancer, pregnancy)

Bauer KA. ASH Education Book. 2013;1:464-470. Majeed A, et al. Circulation 2013;128(21):2325-32.

Outline






Steps to Developing a Bridge Plan

1. Develop plan at least 1 week prior to procedure

2. Evaluate bleeding risk of procedure

3. Evaluate patient’s thrombotic risk

4. Timing of cessation and resumption of agent is based on:

a. Patient’s renal function

b. Half-life/onset of agent

c. Type of procedure and anesthesia

Key Question: Does anticoagulation need to be interrupted?

Assessing Bleed Risk

Baron TH, et al. N Engl J Med 2013;368:2113-24.

Assessing Thrombotic Risk

Blood. 2012;120:2954-62.

Peri-Procedural Management: VKAs

http://qio.ipro.org/wp-content/uploads/2012/12/MAP2014_5_01.pdf

High Bleed Risk

Low Bleed Risk

Minimal Bleed Risk

High thromboembolic

risk

Interrupt VKA, Bridge

Consider interrupting VKA

Bridge

Do not interrupt

VKA

Moderate thromboembolic

risk

Interrupt VKA, Consider bridge

Consider interrupting VKA, Consider bridge

Low thromboembolic

risk

Interrupt VKA, No bridge

Interrupt VKA, No bridge

• Management of Anticoagulation in the Peri-procedural Period (MAP) Tool • Two-Page Summary: Management of Anticoagulation in the Peri-

Procedural Period at http://excellence.acforum.org/

http://excellence.acforum.org/

Peri-Procedural Management: DOACs

Risk Assessment

High Bleed Risk

Low Bleed Risk

Minimal Bleed Risk

High thromboembolic

risk

Interrupt DOAC

Consider interrupting

DOAC

Do not interrupt DOAC

Moderate thromboembolic

risk

Low thromboembolic

risk

Interrupt DOAC


• Management of Anticoagulation in the Peri-procedural Period (MAP) Tool • Two-Page Summary: Management of Anticoagulation in the Peri-

Procedural Period at http://excellence.acforum.org/


Cessation and Resumption of DOACs

• Cessation depends on DOAC, renal function, and bleed risk


Peri-Procedural Management: DOACs

• Resumption of DOAC – similar to LMWH

• Rapid onset of anticoagulant effect (~1-4 hours)

• Caution with resuming too soon or too aggressively

• May consider “step-up” approach

• Lower or prophylactic dose of DOAC for initial 24-48 hours

• If tolerated, increase to treatment dose DOAC at 48-72 hours

Spyropolous AC, et al. Blood 2012; 120(15): 2954-62.

Switching Between Anticoagulants

• Reason for switching from parenteral to oral anticoagulant

–Facilitate longer-term outpatient management

• Reasons for switching from warfarin to DOAC

–Drug intolerance

–Therapeutic failure

–Patient preference

• Reasons for switching from DOAC to warfarin

–Drug intolerance

–Therapeutic failure

–Patient preference

–New comorbidity or contraindication Abo-Salem E, et al. J Thromb Thrombolysis 2014; 37: 372-79.

• Can place patients at undue risk for bleeding or thrombosis

• Requires a “carefully constructed and thoughtful approach” based on:

• Pharmacokinetic profile of each anticoagulant

• Appropriate laboratory assessment of patient’s coagulation status

• Patient’s renal function


Abo-Salem E, et al. J Thromb Thrombolysis 2014; 37: 372-79.

• Unfractionated heparin

–Short half-life precludes need for lag time until alternative anticoagulant is initiated

• DOACs and SQ injectables (LMWH, fondaparinux)

– Longer half-life requires lag time until alternative anticoagulant is initiated

–Start alternative anticoagulant when the next dose of original anticoagulant would be due

• Warfarin

–Extremely long half-life requires confirmed offset via INR

–Slow onset may require overlap of rapid-acting anticoagulant



• DOACs are a viable alternative to

traditional anticoagulants in

appropriately selected patients

– Equal or better efficacy for

VTE treatment and stroke

prevention in NVAF

– Improved safety profile

compared to warfarin

– Significant reduction in major,

fatal, intracranial hemorrhage

– GIB caution: dabigatran and

rivaroxaban

DOAC Summary

• Optimal use of DOACs requires

familiarity with:

–Pharmacokinetic/dynamic

profiles

–Dosing strategies

– Lab measurement

–Peri-procedural strategies

–Switching between agents

–Bleed management

–Reversal strategies

AC Forum- Centers of Excellence


QUESTIONS? Juliann Horne, PharmD

[email protected]

practical management of anticoagulation · practical management of anticoagulation juliann horne,...

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