Updates in Anticoagulation...Updates to Venous Thromboembolism (VTE) Guidelines CHEST. 2016; 149(2): 315-352. 2016 CHEST VTE Guidelines: Select Key Changes Topic New Changed New evidence

Updates in Anticoagulation

Megan Labreck, PharmD, BCPS, CACP

Kristian Navickas, PharmD, BCPS, BCACP

Tara Schreck, PharmD, BCACP

Pharmacist Learning Objectives

At the end of this program, the learner will be able to:

1. Discuss the updates to the 2016 CHEST Guidelines on

Antithrombotic Therapy for VTE Disease

2. Review the current indications and dosing for NOACs

3. Explore the emerging roles of NOACs in CAD, PCI, and

cardioversion

4. Review the updates to the ACC recommendations on the

management of bleeding in patients on oral anticoagulation

Pharmacy Technician Objectives

At the end of this program, the learner will be able to:

1. Understand the similarities and differences

between oral anticoagulants

2. Identify the generic and brand names for oral

anticoagulants

3. State the contraindications to oral anticoagulants

Patient Case

• BC is a 26 yo male diagnosed with a DVT in his left popliteal vein.

• PMH includes a h/o HTN, treated with lisinopril10mg daily (patient admits to non-adherence)

• Patient has commercial insurance through his employer

• Patient admits he recently returned from a trip to New Zealand (spent 20+ hours on airline)

Patient Case

• Things to consider:

– Cause of VTE

– Insurance

– Adherence to medications

• Decisions to make:

– Choice of therapy

– Duration of therapy

A Brief History of Oral

Anticoagulants

• 1930s –

• 1951 – Suicide attempt draws attention to warfarin’s clinical effects

• 1954 – Coumadin approved by Endo Pharmaceuticals

• 1955 – Warfarin given to President Eisenhower after heart attack

• 1980s – INR developed, optimal range introduced

• 1990s – Optimal anticoagulation duration introduced

The Pharmaceutical Journal, Vol. 284, p189 | URI: 10997264

BJH. 2008; 141: 757-761

A Brief History of Oral

Anticoagulants (AC), cont.

• 2000s – First NOACs developed: direct thrombin

inhibitors (DTIs) and Factor Xa inhibitors (FXaIs)

– Ximelagatran halted in 2006 due to liver toxicity

– Dabigatran approved in 2010

– Rivaroxaban approved in 2011

– Apixaban approved in 2012

– Edoxaban approved in 2015

The Pharmaceutical Journal, Vol. 284, p189 | URI: 10997264

BJH. 2008; 141: 757-761

Keeping Safety in Mind

• Joint Commission 2018 National Patient Safety Goals:– NPSG.03.05.01 – Reduce the likelihood of patient harm

associated with anticoagulant therapy

– Use approved protocols for initiation/maintenance

– Baseline INR must be obtained for patients on warfarin, and policies in place for monitoring of anticoagulation

– Provide education regarding anticoagulant therapy to prescribers, staff, patients, and caregivers

The Joint Commission. 2018. https://www.jointcommission.org

Updates to Venous

Thromboembolism (VTE)

Guidelines

CHEST. 2016; 149(2): 315-352

2016 CHEST VTE Guidelines:

Select Key ChangesTopic New Changed New evidence but

no change

Choice of long-term

and extended AC

therapy

ASA for extended

treatment of VTE

Management of

recurrent VTE on

AC therapy

Duration of

treatment

CHEST. 2016; 149(2): 315-352

VTE Risk Factors

• Surgery

• Trauma

• Increasing age

• Obesity

• History VTE

• Cancer

• Immobility

• Pregnancy

• Estrogen-containing oral contraceptives or hormone replacement

• Inherited or acquired thrombophilia

CHEST. 2016; 149(2): 315-352

Photo credit: American Society of Hematology

Choice of AC Therapy - Acute & Long-

Term

• Deep vein thrombosis (DVT) of leg or pulmonary embolism (PE) without active cancer– Extended treatment with NOACs reduce recurrent VTE and is

associated with less bleeding risks

– NOACs preferred over warfarin (Grade 2B)• No one NOAC is preferred over the other

• Rivaroxaban, apixaban (No bridging needed)

• Dabigatran, edoxaban (Start with parenteral AC x5d)

• Warfarin preferred over LMWH (Grade 2C)– Overlap with parenteral anticoagulation x5 days and INR >2 for

24 hours

CHEST. 2016; 149(2): 315-352

Choice of AC Therapy - Acute & Long-

Term, Cont.

• DVT of leg or PE with active cancer

– LMWH preferred over warfarin (Grade 2C)

– LMWH preferred over NOACs (Grade 2C)

– In patients with VTE and cancer who are not treated

with LMWH, there is no preference for either a NOAC

or VKA

CHEST. 2016; 149(2): 315-352

Choice of AC Therapy - Extended

Therapy

• No need to change choice of AC after the first 3

months

• Reassess in periodic intervals

– Annually

• Risk vs Benefit Consideration

– Reduction in recurrent VTE

CHEST. 2016; 149(2): 315-352

AC Considerations for

Initial and Long-Term TreatmentFactor Preferred AC

Cancer LMWH

Parenteral therapy to be avoided Rivaroxaban; apixaban

Once daily oral therapy preferred Rivaroxaban; edoxaban; warfarin

Liver disease and coagulopathy LMWH

Renal disease; CrCl <30mL/min Warfarin

Coronary Artery Disease Warfarin; rivaroxaban; apixaban; edoxaban

Dyspepsia or h/o GI bleeding Warfarin; apixaban

Poor adherence Warfarin

Reversal agent needed Warfarin; UFH

Pregnancy or risk of pregnancy LMWH

Cost Varies

CHEST. 2016; 149(2): 315-352

NOAC Trials in VTE Treatment

ComparisonDabigatran Rivaroxaban Apixaban Edoxaban

Trials RECOVER I

RECOVER II

EINSTEIN DVT

EINSTEIN PE

AMPLIFY HOKUSAI VTE

Study Design Randomized,

double-blind, non-

inferiority, parallel

group

Randomized,

open-label,

event-driven, non-

inferiority, parallel

group

Randomized,

double-blind,

parallel group

Randomized,

double-blind, non-

inferiority parallel

group

Primary Efficacy

Endpoint

Recurrent

symptomatic VTE

or death related

VTE

Recurrent

symptomatic VTE

Recurrent

symptomatic VTE

or death related

VTE

Recurrent

symptomatic VTE

Primary Safety

Endpoint

Major bleeding Major or CRNM

bleeding

Major bleeding Major or CRNM

bleeding

Drugs. 2014;74:2015-32.



Sample Size (n) 5107 8281 5395 8240

% DVT Patients 69% 99% (EINSTEIN DVT) 66% 60%

% PE Patients 22% 75% (EINSTEIN PE) 25% 30%

% PE and DVT

Patients

9% 15% 9% 10%

% Active Cancer 4% 5% 3% 3%

% Unprovoked N/A 63% 90% 66%

Drugs. 2014;74:2015-32.



Intervention 150mg BID

150mg BID

15mg BID x21

days → 20mg

once daily

10mg BID x7 days

→ 5mg BID

60mg or 30mg

once daily

Comparator Warfarin Enoxaparin →

warfarin

Enoxaparin →

warfarin

Warfarin

Parenteral AC (UFH, LMWH,

fondaparinux)

Mandatory, ≥5 day Optional, max 48h Optional, max 36h Mandatory, ≥5 day

Duration of

Treatment

6 mos 3, 6, or 12 mos 6 mos 3, 6, or 12 mos

Drugs. 2014;74:2015-32.



Primary efficacy

endpoint (%)

2.4 vs 2.1

2.3 vs 2.2

2.1 vs 3

2.1 vs 1.8

2.3 vs 2.7 3.2 vs 3.5

Major Bleeding

(%)

1.6 vs 1.9

1.2 vs 1.7

0.8 vs 1.2

1.1 vs 2.2

0.6 vs 1.8 1.4 vs 1.6

CRNM Bleeding

(%)

4 vs 6.9

3.8 vs 6.2

7.3 vs 7

9.5 vs 9.8

3.8 vs 8 7.2 vs 8.9

Major and CRNM

Bleeding (%)

5.6 vs 8.8

5 vs 7.9

8.1 vs 8.1

10.3 vs 11.4

4.3 vs 9.7 8.5 vs 10.3

Drugs. 2014;74:2015-32.

Aspirin (ASA) for Extended

treatment of VTE

• In patients with an unprovoked DVT or PE who are stopping AC treatment and have no contraindication to ASA:– ASA preferred over no ASA (Grade 2C)

– Study population = patients completing 3 months of initial AC therapy after 1st unprovoked DVT/PE

– Less effective at preventing recurrent VTE than anticoagulants

– Balance with ASA’s risk of bleeding and inconvenience

– Better than no therapy

CHEST. 2016; 149(2): 315-352.

Management of VTE Despite AC

Therapy

• If on therapeutic warfarin or NOAC, then switch to LMWH temporarily (minimum 1 month) (Grade 2C)

• If on long-term LMWH and compliant, recommendation is to increase the dose by 25-33% (Grade 2C)

• Reason for recurrence– Non-adherence

– Subtherapeutic warfarin

– Drug interaction (reducing AC effect)

– Patient factors (active cancer, antiphospholipid syndrome, hormones)

CHEST. 2016; 149(2): 315-352.

Duration of AC Treatment Based on

Type of VTEType of VTE Recommended Duration of

Treatment 2012

Recommended Duration of

Treatment 2016

Proximal DVT (leg) or PE

provoked by surgery

3 months 3 months

DVT (leg) or PE provoked by

nonsurgical transient risk factor

3 months 3 months

Isolated distal DVT (leg)

provoked by surgery or

nonsurgical transient risk factor

3 months 3 months

Unprovoked PE or DVT (leg) At least 3 months At least 3 months

Pt’s first DVT that is an

unprovoked proximal DT (leg)

or PE

At least 3 months Extended therapy (no

scheduled stop date)

CHEST. 2016; 149(2): 315-352.

Duration of AC Treatment Based on

Type of VTEType of VTE Recommended Duration of

Treatment 2012

Recommended Duration of

Treatment 2016

In patients with second

unprovoked VTE with a low

bleeding risk

Recommended extended

therapy

Extended therapy (no scheduled

stop date)


unprovoked VTE with a

moderate bleeding risk

Suggested extended therapy At least 3 months


unprovoked VTE with a high

bleeding risk

Suggest 3 months 3 months

Patients with DVT (leg) and

active cancer w/ or w/o high risk

of bleeding

Extended therapy Extended therapy (no scheduled

stop date)

CHEST. 2016; 149(2): 315-352.

Review: NOAC Indications

and Dosing

PHOTO CREDIT:

HTTPS://WWW.NATURE.COM

NOAC: Renal Exclusions

• Dabigatran:

– Avoid in CrCl <15 mL/min

• Rivaroxaban:

– Avoid non-valvular AF treatment in CrCl <15 mL/min

– Avoid DVT/PE treatment and prophylaxis in CrCl <30

mL/min

Pradaxa (dabigatran) [prescribing information]. Ridgefield, CT:

Boehringer Ingelheim Pharmaceuticals, Inc; August 2014.

Xarelto (rivaroxaban) [prescribing information]. Gurabo, PR:

Janssen Pharmaceuticals Inc; September 2014.

NOAC: Renal Exclusions

• Apixaban:

– DVT/PE Treatment excluded CrCl <25 mL/min or SCr>2.5 from trials

– DVT prophylaxis excluded CrCl <30 mL/min from trial

• Edoxaban:

– Avoid non-valvular AF treatment in CrCl <15 mL/min or >95 mL/min

– Avoid DVT/PE treatment in CrCl <15 mL/min

Eliquis (apixaban) [prescribing information]. Princeton,

NJ: Bristol-Myers Squibb; March 2014.

Savaysa (edoxaban) [prescribing information]. Tokyo,

Japan: Daiichi Sankyo; January 2015.

NOAC: Half-Life

• T1/2 much shorter than warfarin

– Compliance is crucial to NOAC success

Dabigatran Apixaban Edoxaban Rivaroxaban

T1/2 (hours) 12-17 12 10-14 9-13

Cost Comparison; Monthly

• Dabigatran: $387

• Rivaroxaban: $425

• Apixaban: $425

• Edoxaban: $342

• Warfarin: $4

• PT/INR (self pay): $17.55

Drug prices obtained from www.goodrx.com

Betrixaban – New NOAC

• Direct factor Xa inhibitor

• Indication: VTE prevention– Acutely ill medical, non-surgical patients

– Moderate or severely limited mobility plus other VTE risk factors

• Not recommended for use in AF, VTE treatment, after hip/knee surgery, long-term VTE prevention in cancer or prior VTE

Product information for Bevyxxa. Portola Pharmaceuticals.

South San Francisco, CA 94080. March 2018.


• LMWH → 160mg x1 then 80mg once daily with food for 35-42 days

• Renal dosing: 80mg x1 then 40mg once daily with food for 35-42 days

• APEX clinical trial – prevents small number of symptomatic VTEs, increases risk of CRNM

• Expensive ($630 for 6 weeks therapy)



Emerging Roles of NOACs

NOACs in CAD: COMPASS Trial

• Clinical question

– In patients with established stable atherosclerotic

disease, is rivaroxaban plus aspirin more effective

than aspirin alone in reducing cardiovascular

death, stroke, or nonfatal MI?

NEJM. 2017; 377(14): 1319-1330.

NEJM. 2017; 377(14): 1319-1330.

COMPASS Summary

• Rivaroxaban dose is vascular dose

• Rivaroxaban 2.5mg twice daily + aspirin 100mg

daily

– Reduces CV death, stroke, MI

– Increases major bleeding without a significant

increase in fatal or intracranial bleeding

– No significant benefit vs. rivaroxaban alone

NEJM. 2017; 377(14): 1319-1330.

COMPASS Summary

• Rivaroxaban dose is vascular dose

• Rivaroxaban 2.5mg twice daily + aspirin 100mg

daily

– Reduces CV death, stroke, MI

– Increases major bleeding without a significant

increase in fatal or intracranial bleeding

– No significant benefit vs. rivaroxaban alone

NEJM. 2017; 377(14): 1319-1330.

Take Away:

Rivaroxaban dose is not approved worldwide

Early termination: this may overestimate the

degree of benefit of riva+aspirin

NOACs in PCI: RE-DUAL PCI

• Clinical question– In patients with nonvalvular atrial fibrillation (AF)

undergoing percutaneous coronary intervention (PCI) for coronary artery disease, is dual therapy with a thienopyridine antiplatelet and dabigatran associated with less bleeding when compared to triple therapy with aspirin, a thienopyridine antiplatelet, and dabigatran? Is dual therapy associated a higher rate of thrombosis?

NEJM. 2017; 377(16): 1513-1524.

NEJM. 2017; 377(16): 1513-1524.

RE-DUAL PCI: Summary

• In AF patients who underwent PCI– Dabigatran + P2Y12 (dual therapy) antagonist significantly reduced risk of

bleeding vs. warfarin triple therapy

– Non-inferiority for thrombotic events

– Dabigatran doses used are (110mg vs 150mg) approved worldwide for stroke prevention

• LIMITATIONS– The initial goal sample size of 8520 patients (powered to assess for

thromboembolic events) was not reached due to feasibility. As a result, the trial is underpowered to robustly assess for thrombotic events.

– Only 12% of study patients received ticagrelor, limiting generalizability of these findings to use of this drug.

NEJM. 2017; 377(16): 1513-1524.

RE-DUAL PCI: Summary

• In AF patients who underwent PCI– Dabigatran + P2Y12 (dual therapy) antagonist significantly reduced risk of

bleeding vs. warfarin triple therapy

– Non-inferiority for thrombotic events

– Dabigatran doses used are (110mg vs 150mg) approved worldwide for stroke prevention

• LIMITATIONS– The initial goal sample size of 8520 patients (powered to assess for

thromboembolic events) was not reached due to feasibility. As a result, the trial is underpowered to robustly assess for thrombotic events.

– Only 12% of study patients received ticagrelor, limiting generalizability of these findings to use of this drug.

NEJM. 2017; 377(16): 1513-1524.

Take Away:

Dabigatran + P2Y12 (dual therapy) is non-inferior

to triple therapy and may be an option in AF

patients undergoing PCI

NOACs in PCI: PIONEER-AF PCI

• Clinical question

– Among patients with nonvalvular AF undergoing PCI

with stent placement, does low-dose rivaroxaban plus

either single or dual antiplatelet therapy reduce risk of

bleeding when compared to warfarin plus dual

antiplatelet therapy?

NEJM. 2016; epub Nov 2016: 1-12.

NEJM. 2016; epub Nov 2016: 1-12.

PIONEER-AF PCI Summary

• In patient with AF undergoing PCI for stent placement– Rivaroxaban based therapy was associated with less clinically

significant bleeding

– TIMI major bleeding was similar between the three groups

– Major ADE (ie: cardiac events, stent thrombosis) was similar between groups

– All cause mortality and re-hospitalization was lower with rivaroxaban vs. warfarin/DaPT

• Limitations– Not blinded, not powered for efficacy, smaller sample size than

NOAC trials

NEJM. 2016; epub Nov 2016: 1-12.

PIONEER-AF PCI Summary

• In patient with AF undergoing PCI for stent placement– Rivaroxaban based therapy was associated with less clinically

significant bleeding

– TIMI major bleeding was similar between the three groups

– Major ADE (ie: cardiac events, stent thrombosis) was similar between groups

– All cause mortality and re-hospitalization was lower with rivaroxaban vs. warfarin/DaPT

• Limitations– Not blinded, not powered for efficacy, smaller sample size than

NOAC trials

NEJM. 2016; epub Nov 2016: 1-12.

Take Away:

Rivaroxaban based therapy had less clinically

significant bleeding compared to VKA based

therapies.

Not powered for efficacy- is this clinically

significant?

NOACs in Cardioversion: EMANATE

• Clinical Question:

– The goal of the trial was to evaluate short-duration

apixaban compared with warfarin with among patients

undergoing cardioversion.

Am Heart Journal. 2016; 179: 59-68.



EMANATE Trial Summary

• Bleeding rates were similar across both the

apixaban and warfarin groups.

• EMANATE was underpowered

– Their findings “support the use of apixaban in patients

with AFib undergoing cardioversion.”


EMANATE Trial Summary

• Bleeding rates were similar across both the

apixaban and warfarin groups.

• EMANATE was underpowered

– Their findings “support the use of apixaban in patients

with AFib undergoing cardioversion.”


Take Away:

This study supports the use of apixaban prior to

cardioversion.

Stay tuned for full publication

Managing Bleeding

New Guidance for Managing

Bleeding

• American College of Cardiology (ACC) released expert consensus decision pathway in 2017

• Provides guidance to clinicians who are managing bleeding in the setting of warfarin and NOACS

• Considers:– Severity of bleeding

– Acute medical and surgical management

– Need for reversal

– Appropriateness of restarting anticoagulation

JACC. 2017; 70(24): 3042-4067

Assessment and Treatment

Strategies

• Major bleeding:– Bleeding at critical site

– Hemodynamically unstable

– Clinically overt bleeding

• Minor bleeding: Everything else

• Treatment recommendations:– Major bleeding: Stop OAC, initiate appropriate measures to stop

bleeding

– Minor bleeding: Stop OAC in patients requiring hospitalization, a surgical intervention, or a transfusion

JACC. 2017; 70(24): 3042-4067

Laboratory Assessment

• All anticoagulated patients: PT and aPTT

• VKA: INR

• Dabigatran: Dilute thrombin time, ecarin clotting time, ecarin chromogenic assay– Thrombin time (TT): Normal value can rule out relevant

dabigatran levels

• FXa-Inhibitors: Chromogenic anti-Xa assay, PT (edoxaban and rivaroxaban)

JACC. 2017; 70(24): 3042-4067

Assessment and Treatment

Strategies

VKA (Warfarin) DTI (Dabigatran)

FXa-Inhibitors (Apixaban,

edoxaban, rivaroxaban)

-Vitamin K oral (non-major) or

IV (major/critical)

-Consider activated charcoal

for ingestion w/in 2-4 hours

-Consider activated charcoal

for ingestion w/in 2-4 hours

-Administer 4F-PCC

-INR 2-4: 25u/kg

-INR 4-6: 35u/kg

-INR >6: 50u/kg

-Administer 5g idarucizumab

IV

-Administer 4F-PCC 50u/kg IV

- Alternative 4F-PCC dosing

-Low fixed-dose option

(1000units)

-1500u for ICH

-If idarucizumab IV not

available, administer 4F-PCC

or aPCC 50u/kg IV

-If 4F-PCC not available,

administer aPCC 50u/kg IV

JACC. 2017; 70(24): 3042-4067

Patient Case – Remember BC?

• Things to consider:

– Cause of VTE – likely related to his travel (provoked

cause)

– Insurance (high-deductible not met)

– Patient endorses a desire to improve adherence and

overall health, thinks he might be more successful

with once-daily therapy.


• Which choice of therapy is recommended for BC

at this time?

A. Weight-based LMWH

B. Warfarin

C. NOAC (no specific agent preferred)

D. NOAC (specific agent preferred)


• Which duration of anticoagulation therapy is

recommended for BC at this time?

A. Indefinite

B. At least 3 months

C. At least 1 year

D. At least 2 weeks, then reevaluate

Patient Case – Remember BC

• Should BC be on ASA after his anticoagulation therapy is complete?– Guidelines recommend after first 3 months (grade 2C)

– Studies involved 1st unprovoked VTE

• Does BC need bridging with LMWH prior to starting oral anticoagulation?– No – rivaroxaban, apixaban

– Yes – dabigatran, edoxaban

Updates in Anticoagulation

Megan Labreck, PharmD, BCPS, CACP

Kristian Navickas, PharmD, BCPS, BCACP

Tara Schreck, PharmD, BCACP


• Direct factor Xa inhibitor

• Indication: VTE prevention– Acutely ill medical, non-surgical patients

– Moderate or severely limited mobility plus other VTE risk factors

• Not recommended for use in AF, VTE treatment, after hip/knee surgery, long-term VTE prevention in cancer or prior VTE




• LMWH → 160mg x1 then 80mg once daily with food for 35-42 days

• Renal dosing: 80mg x1 then 40mg once daily with food for 35-42 days

• APEX clinical trial – prevents small number of symptomatic VTEs, increases risk of CRNM

• Expensive ($630 for 6 weeks therapy)



Documents

Updates in Anticoagulation...Updates to Venous Thromboembolism (VTE) Guidelines CHEST. 2016; 149(2): 315-352. 2016 CHEST VTE Guidelines: Select Key Changes Topic New Changed New evidence