Updates in Coagulation Thrombophilia testing and

direct oral anticoagulants

Kevin Y. Chen, MD

Hematology and Medical Oncology

October 13, 2017

No conflicts of interest

Introduction to thrombosis

Hemostasis

Coagulation cascade

Virchow’s triad

Overview of Acute Venous Thromboembolism

Annual incidence in U.S. = 1-2/1000 general population

Incidence increases dramatically with age >60

Standard therapy (3 or more months of anticoagulation)

Decreases the short-term recurrence rate from ~25% to ~3%

Associated with major bleeding (~1-2%/year of treatment with

warfarin)

Recurrence after stopping anticoagulation 1 year 5years Provoked by surgery ~1% ~3%

Provoked by non-surgical reversible risk factors ~5% ~15%

(e.g., estrogen, pregnancy, leg injury, flight >8 hours)

Unprovoked ~10% ~30%

Active cancer ~15%/year

American College of Chest Physicians

2016 Guidelines for Treatment of VTE Kearon C et al., Chest 2012; 141(2 Suppl): e419S-494S (9th Edition)

Kearon C et al., Chest 2016 Feb; 149(2): 315-352 (10th Edition)

Recommendations Evidence

Strong (Grade 1)

Weak (Grade 2)

High-quality (Grade A)

Moderate-quality (Grade B)

Low-quality (Grade C)

Graded recommendations for: Proximal lower extremity DVT and PE

PE with hypotension

Distal lower extremity DVT

Superficial venous thrombosis

Upper extremity DVT

Post-thrombotic syndrome

Catheter-associated thrombosis

Splanchnic and hepatic vein thrombosis

Chronic thromboembolic pulmonary hypertension

Acute Proximal DVT or PE

Initial Treatment Grade

For initial treatment with heparin, suggest LMWH or

fondaparinux over IV unfractionated heparin (IV UFH preferred in patients with severe renal failure or those undergoing

thrombolysis)

2B/2C

If using warfarin, initiate therapy on day 1

Continue parenteral AC for ≥5 days and until the INR ≥2.0 for

≥24 h

1B

IVC filter

Use only in patients with a contraindication to

anticoagulation

Begin a conventional course of AC if the risk of bleeding

resolves

(A permanent IVC filter is no longer considered to be an indication for

extended AC)

1B

2B

Acute Proximal DVT or PE

* new in 2016 guidelines

Choice of Anticoagulant Grade

VTE and no cancer

Suggest a DOAC over warfarin *

In patients not treated with a DOAC, suggest warfarin over

LMWH (target INR 2.0-3.0 for all treatment durations)

2B

2C

VTE and active cancer

Suggest LMWH over warfarin or a DOAC *

2C

VTE and pregnancy

Suggest LMWH over UFH (warfarin is teratogenic, esp. 1st

TM)

Discontinue ≥24 h prior to induction or C-section

1B

1B

* new in 2016 guidelines

Duration of Treatment for Acute VTE

Depends on estimation of:

(1) Risk of recurrence

Provoked by surgery

Provoked by non-surgical reversible risk (e.g., estrogen, pregnancy, leg injury, flight >8 hours)

First unprovoked VTE

Active cancer/ Second unprovoked VTE

(2) Risk of bleeding

~1%/y

~15%/y

Estimation of Bleeding Risk (not validated prospectively)

Risk factors Bleeding Risk

Age >65

Age >75

Previous bleeding

Cancer

Metastatic cancer

Renal failure

Liver failure

Thrombocytopenia

Previous stroke

Diabetes

Anemia

Antiplatelet therapy

Poor anticoagulant control

Comorbidity and reduced functional

capacity

Recent surgery

Frequent falls

Alcohol abuse

NSAID use (added in 2016)

“Low” 0 risk

factors

“Moderate”1 risk

factor

“High” ≥2 risk

factors

Estimation of Bleeding Risk

Major Bleeding After VTE (most studies assessed risk on warfarin therapy)

Initial 3 Months (%) Extended >3 Months (%/y)

Acute Proximal DVT or PE

Duration of Treatment (symptomatic=incidental)

Grade

VTE provoked by

Surgery

Non-surgical transient risk factor

3 months

3 months

1B

1B

1st unprovoked VTE

Low/moderate bleeding risk

High bleeding risk

Indefinite

3 months

2B

1B

2nd unprovoked VTE

Low/moderate bleeding risk

High bleeding risk

Indefinite

3 months

1B/2B

2B

VTE and active cancer

Low/moderate bleeding risk

High bleeding risk

Indefinite

Indefinite

1B

2B

VTE during pregnancy

Continue until

6 wk postpartum

(3 mo minimum)

2C

Hypercoagulable work up

“Although inherited and acquired thrombophilias

are acknowledged to increase the risk of VTE,

the majority of patients should not be tested for

thrombophilia.”

“Some arguing that these tests should never be

performed.”

NEJM, Connors, 2017

570 patients with first VTE

followed prospectively

85% had thrombophilia testing

(after anticoagulation stopped)

Recurrence rate 11%

Recurrence rate not related to

inherited thrombophilia status:

Hazard ratio 1.5 (.82-2.77)

J Thromb Haemost 2008;6:1474

Case control study of 197

patients who had

recurrence after first VTE

and 324 control patients

Primary endpoint: Odds

ratio of recurrent

thrombosis based on those

tested and those not tested

What are the issues with testing?

•No data supporting benefit of testing to guide

secondary or primary prophylaxis

•Results may not alter management

•Negative testing does not equate low risk

•Current tests are insufficient

•Accuracy of some testing is dependent on

timing

Other testing:

MPN testing (JAK2, CALR,

MPL, BCR-ABL)

PNH testing (FLAER)

Elevated Factor VIII

Elevated Factor IX

Elevated Factor XI

Elevated plasminogen activator

inhibitor -1 (PAI-1)

PAI-1 promoter polymorphism

MTHFR polymorphism (677C-

>T, 1298A->C)

NEJM, Connors, 2017

Inherited thrombophila

Clinical characteristics

NEJM, Connors, 2017

Antiphospholipid antibody syndrome

NEJM, Connors, 2017

Inherited thrombophila and pregnancy

Recommendations

Clinical scenarios

A 33 year old male with no medical problems

suffers a fractured femur playing football. He

has surgery, but 1 week later develops calf

swelling and is found to have a DVT. His 65

year old mother was recently found to have PE

and was diagnosed with breast cancer.

Clinical scenarios

A 23 year old with 2 younger sisters develops a

DVT while 28 weeks pregnant. Her mother had

a spontaneous PE when she was in her 30s.

Clinical scenarios

A 36 year old female in her usual state of health

is admitted into the ICU and found to have

bilateral PE. She has a depressed EF and is

given thrombolytics. Her aunt also had DVTs in

her thirties

Algorithm for testing

854 patients randomized to limited

cancer screening vs limited cancer

screening with body CT

Cancer detection: 3.2% vs 4.5%

Cancers missed: 4 vs 5

Time to cancer diagnosis: 4.2mos vs

4.0mos

Cancer related mortality: 1.4% vs 0.9%

1818 patient with unprovoked DVT treated

with coumadin

Cox regression to determine factors for

recurrence

DASH SCORE

- D: post-anticoagulation D-Dimer (+2)

- A: Age < 50 (+1)

- S: Male (+1)

- H: Hormone use (-2)

Annual risk of recurrence

1 or less: 2.1%

2: 6.4%

3+: 12.3%

•3365 patients with VTE and had completed 6-

12 months of treatment randomized to 20mg

rivaroxaban, 10mg rivaroxaban, 100mg ASA

•Primary outcome recurrent VTE, safety

outcome of major bleeding

Recurrent VTE

- 20mg (1.5%)

- 10mg (1.2%)

- ASA (4.4%)

Major Bleeding

- 20mg (0.5%)

- 10mg (0.4%)

- ASA (0.3%)

Non major bleeding

- 20mg (2.7%)

- 10mg (2.0%)

- ASA (1.8%)

Take home points

•Thrombophilia testing is often not indicated

•May be clinically relevant in select patients

(especially APLAB)

•Testing should not be done at time of acute

event

•Clinical factors more relevant for duration of

anti-coagulation

•Consider age appropriate cancer screening

•Long term low dose anticoagulation may be an

option for intermediate risk patients

Direct oral anticoagulants

“If these novel breakthrough oral anticoagulant

drugs prove to be effective across the broad

spectrum of patients in routine care and are

conscientiously priced, the worldwide impact will

be huge.”

NEJM, Hylek, 2010

Betrixaban FDA approved 2017

Direct Oral Anticoagulants

Bind reversibly to the catalytic sites of their target proteases

Rivaroxaban

Dabigatran etexilate (prodrug)

Dabigatran (active drug)

In vivo

Apixaban

Edoxaban

Thrombin Factor Xa

Coagulation cascade

Anthrombin mediated

inhibitor of Xa, Iia

- UFH

- LMWH

- Fondaparinaux

Vitamin K Antagonist

- Warfarin

Direct thrombin inhibitor

- Argatroban

- Bivalrudin

- Dabigatran

Factor Xa inhibitor

- Rivaroxaban

- Apixaban

- Edoxaban

- Betrixiban

Dabigatran

(Pradaxa)

Rivaroxaban

(Xarelto)

Apixaban

(Eliquis)

Edoxaban

(Savaysa)

Target Thrombin Xa Xa Xa

Bioavailability 7% 80% (with food) 60% 60%

Peak action 0.5-3 hours 2-4 hours 1-3 hours 1-2 hours

Half-life 14-17 hours 7-12 hours 8-15 hours 10-14 hours

Renal clearance

80% 33% 25% 50%

Interactions P-gp P-gp

CYP3A4

P-gp

CYP3A4 P-gp

Dosing Twice daily Twice then once daily

Twice daily Once daily

Initial parenteral anticoagulation

5-10 days of heparin/LMWH

None None 5-10 days of heparin/LMWH

Monitoring None None None None

Direct Oral Anticoagulants

Dabigatran

•Dose

–Stroke prevention in A fib: 110-150 mg bid

•110 mg dose not available in US

•For patients with CrCl 15-30: 75 mg bid

•Not recommended for CrCl < 15 or dialysis dependent

–Postop VTE prophylaxis*: 150-220 mg once daily

–VTE treatment/prevention of recurrent VTE: 150 mg bid (following

LMWH or heparin Rx)

•Less than 10% absorbed; relatively high rate of GI side effects

•Crosses the placenta – do not use during pregnancy

•Drug may degrade over time after exposure to air – must be kept in

original packaging

Rivaroxaban

•Dose:

–Stroke prevention in nonvalvular Afib: 15-20 mg

once daily

–Post op VTE prophylaxis: 10 mg once daily

–Acute VTE treatment: 15 mg twice daily

–Secondary prevention of VTE: 20 mg once daily or

10mg daily after 6 months

–Acute coronary syndrome*: 2.5-5 mg twice daily

•Use with caution in moderate renal impairment (CrCL

30-49); 15 mg/day dose recommended

–Avoid use if CrCl < 30 (not dialyzable)

•Avoid use in severe liver disease

Apixaban

•Dose:

–Stroke prevention in nonvalvular Afib: 5 mg bid

•2.5 mg bid if age >80, weight < 60 kg, or serum

creatinine > 1.5

–Post op VTE prophylaxis: 2.5 mg bid

–Treatment of acute VTE: 10 mg bid x 7 days, then 5

mg bid

–Secondary prevention of VTE: 2.5 mg bid after 6

months

•Lowest dependence on renal excretion of new agents

•Avoid use in severe liver disease (75% biliary excretion)

Edoxaban

•Dose:

–Stroke prevention in Afib: 60 mg/d

•30 mg/d if CrCl 15-50 or body wt ≤ 60 kg

–Post op VTE prophylaxis*: 30 mg/d

–Treatment of acute VTE: 60 mg/d (following LMWH

or heparin Rx)

➢Avoid use if CrCl > 95 ml/min (excessive excretion

decreases efficacy)

Betrixaban

•Dose:

–VTE (prophylaxis): Oral: 160 mg as a single dose

on day 1, followed by 80 mg once daily for 35 to 42

days

– Reduce betrixaban dose (initial and maintenance)

by 50% for patients receiving or starting P-

glycoprotein inhibitors (eg, amiodarone,

azithromycin, clarithromycin, ketoconazole,

verapamil).

– Severe renal impairment: avoid use

Efficacy of DOACs for treatment of acute VTE

J Thromb Haemost 2014;12:320

J Thromb Haemost 2014;12:320

Safety of DOACs for treatment of acute VTE

DOACS in atrial fibrillation

Ruff et al, Lancet 2013

Dabigatran 150 mg bid

Rivaroxaban 20 mg qd

Apixaban 5 mg bid

Edoxaban 60 mg qd

Combined

J Thromb Haemost 2014;12:107

Symptomatic VTE

Total VTE +

All-cause mortality

Major bleeding

DOACs in VTE prophylaxis after total hip

arthroplasty

Dabigatran

(Pradaxa)

Rivaroxaban

(Xarelto)

Apixaban

(Eliquis)

Edoxaban

(Savaysa)

Betrixaban (Bevyxxa)

Non-valvular a fib stroke

prophylaxis ✔ ✔ ✔ ✔

Initial DVT/PE treatment ✔ after 5-10

d heparin ✔ ✔ ✔ after 5-10

d heparin

Extended-duration

DVT/PE treatment ✔ ✔ ✔

Knee replacement VTE

prophylaxis ✔ ✔

Hip replacement VTE

prophylaxis ✔ ✔ ✔

Hip fracture VTE

prophylaxis

Medical VTE prophylaxis ✔

Acute coronary

syndrome

Heparin-induced

thrombocytopenia

FDA-approved Indications

Drug effects on coagulation tests

•PT/INR and PTT are relatively insensitive to the

effects of DOACs

–Reagent-dependent – results will vary among labs

•Normal PT and PTT do not rule out significant

blood level of DOAC

•If PT or PTT elevated → assume significant

blood levels of DOAC

•Thrombin time very sensitive to dabigatran

effect – normal TT implies no drug on board

–Direct Xa inhibitors do not affect TT

Monitoring

•Dabigatran:

–Modified thrombin time assay (Hemoclot®)

•Rivaroxaban, apixaban, edoxaban:

–Anti-Xa activity (similar to LMWH assay)

•Neither assay FDA-approved or widely available now

•When to consider measuring drug level:

–Detect/quantify overdose

–Screen for drug accumulation (eg, impaired renal or liver

function)

–Assure low drug level prior to surgery

➢Limited usefulness for assessing compliance due to

short drug half-lives

Reversal agents

Blood 2014;124(15):2450-2458

Data from 12 RCTs of DOACs involving 102,607 patients

Major bleeding

RR 0.72

[0.62-0.85]

Fatal bleeding

RR 0.53

[0.43-0.64]

Intracranial bleeding

RR 0.43

[0.37-0.50]

Major GI bleeding

RR 0.94

[0.75-1.19]

Risk Ratios Comparing DOACs to Warfarin

Kaatz et al. Am J Hematol 2012; 87: S141-5

Reversal of Direct Oral Anticoagulants

(<2 h)

(?) (?)

Eerenberg et al. Circulation 2011; 124(14): 1573-9

Reversal of Rivaroxaban by 4-factor PCC (50

IU/kg)

in Healthy Volunteers

Rivaroxaban

PT

Dabigatran

aPTT

Dabigatran

Thrombin time

placebo

PCC

Idarucizumab (Praxbind) for Dabigatran Reversal

Pollack et al., N Engl J Med 2015 Aug 6;373(6):511-20

Idarucizumab (Praxbind®) is a monoclonal antibody fragment

that binds to dabigatran with high affinity (350x that of

thrombin)

5 mg of idarucizumab (2 x 2.5 mg vials) completely reverses

the anticoagulant effect of dabigatran when the drug is taken

at usual recommended doses

This effect occurs within minutes of drug administration and

restores normal hemostasis (NEJM 2015; 373:511)

Idarucizumab approved by FDA in October 2015

• 503 patients enrolled, 301 uncontrolled

bleeding, 202 required urgent procedure

• Primary end point reversal measure by dilute

thrombin time

• Median maximum percentage reversal was

100%

• Median time to cessation of bleeding 2.5 hours,

median time to procedure 1.6 hours

Idarucizumab (Praxbind) for Dabigatran Reversal

Figures from Nature Medicine 19, 402-4 (2013)

Andexanet alfa for Reversal of Xa Inhibitors

Recombinant factor Xa variant Lacks the γ-carboxyglutamic acid domain required for phospholipid binding

Alanine substituted for serine in the active site (catalytically inactive)

Andexanet alfa for Reversal of Xa Inhibitors

Siegal et al., N Engl J Med 2015 Dec 17;373(25):2413-24

Study Design

Healthy volunteers (50-75 years old) housed at a study site for 8 days

Apixaban study: 5 mg PO BID x 3.5 days, then Andexanet 400 mg IV bolus +/- 4

mg/min continuous IV infusion for 2 h OR placebo

Rivaroxaban study: 20 mg PO QD x 4 days, then Andexanet 800 mg IV bolus +/-

8 mg/min continuous IV infusion for 2 h OR placebo

Primary outcome: percent change in anti-factor Xa activity

Bolus plus infusion

Andexanet alfa for Reversal of Xa Inhibitors

Siegal et al., N Engl J Med 2015 Dec 17;373(25):2413-24

Conclusions

Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban within

minutes

Rapid onset and offset of action (provides flexibility of treatment?)

No serious adverse events (1 patient with hives)

No antibodies against factor X or Xa detected at 43 days

Andexanet alfa for Reversal of Xa Inhibitors

Siegal et al., N Engl J Med 2015 Dec 17;373(25):2413-24

67 patients with acute major bleeding within 18

hours of receiving anti Xa inhibitor

• Mean time from ED arrival to rx: 4.8 hours

• Decrease in antiXa activity:

–89% and 93% (after bolus, during 2hour infusion)

–39% and 30% (4 hours after infusion complete)

• Good/excellent clinical hemostasis 12 hours after: 79%

• Thrombotic event rate: 18% at 30 days

Transition to DOAC

•Unfractionated heparin to DOAC:

–Start DOAC when UFH infusion stopped

•LMWH to DOAC:

–Start DOAC 2 h before next scheduled sq dose of

LMWH

•Warfarin to DOAC:

–When INR < 2.0

Transition from DOAC

•DOAC to parenteral anticoagulant:

–CrCl >30: start 12 hours after last NOAC dose

–CrCl <30: start 24 hours after last NOAC dose

•DOAC to warfarin:

–CrCl >50: start warfarin 3 days before NOAC

stopped

–CrCl 31-50: start warfarin 2 days before NOAC

stopped

–CrCl 15-30: start warfarin 1 day before NOAC

stopped

➢Remember that NOACs can prolong PT/INR

Perioperative management

•Stop DOAC at least 3 drug half-lives prior to

surgery

–Dabigatran: 42-51 h

–Rivaroxaban: 15-27 h

–Apixaban: 24-48 h

•Allow more time if:

–Age > 75

–Impaired renal or liver function

–High bleeding risk

Recurrent VTE While on Anticoagulation

Approach to Treatment Grade

If recurrence on warfarin or a DOAC

Evaluate for true recurrence, compliance, or

malignancy

Switch to LMWH for at least 1 month *

2C

If recurrence on long-term LMWH and patient is

compliant

Increase dose of LMWH by 25% to 33% *

2C

* new in 2016 guidelines

Cost per month

• Rivaroxaban (20 mg/day) : $290

• Dabigatran (150 mg bid): $290

• Apixaban (5 mg bid): $147

• Warfarin (7.5 mg/day): $31

Patients selection for DOAC

• Patients who have unstable INR on warfarin

not due to poor compliance

• Adequate renal & hepatic function

• No mechanical valve

• Not pregnant (drugs cross placenta)

• Not at extremes of weight (can’t adjust dose)

• Not at high risk of lower GI bleeding