Ravi Sarode, MD

Professor of Pathology

Chief of Pathology and Medical Director of Clinical Laboratory Services

Director, Transfusion Medicine and Hemostasis

UT Southwestern Medical Center, Dallas, TX

Review of Newer Antiplatelets,

Antithrombotics and Reversal

SVIN Hollywood, FL, November 7, 2014

Disclosures

Consultant CSL Behring

Advisor Octapharma

Off label use of drugs – PCC and

rFVIIa

Please don’t show

coagulation

cascade!!!

Sites of action of Oral Anticoagulants

TF + VIIa

FX

FIX

FXa

FIIa

FIXa FVIIIa

FII

Rivaroxaban

Apixaban

Dabigatran

etexilate

Warfarin

Evolution of Oral

Anticoagulation Therapy

Warfarin to Dabigatran to Rivaroxaban to Apixaban to……..

Dabigatran

Etexilate

(Pradaxa)

Rivaroxban

(Xarelto)

Apixaban

(Eliquis)

MOA Direct

Thrombin

inhibitor

Direct FXa

inhibitor

Direct FXa

inhibitor

Manufacturer Boehringer

Ingelheim

Bayer

Bristol Myers

and Sqibb

Indications 1. Reduce risk

of stroke and

TE in NV-AF

2. Treatment and

prophylaxis of

DVT/PE

1. Reduce risk of

stroke and TE in

NV-AF

2. Rx of DVT and

PE

3. DVT

prophylaxis

1. Reduce risk

of stroke and

TE in NV- AF

2. Rx DVT and

PE

3. DVT

prophylaxis

Target Specific Oral Anticoagulants

RE-LY Study

(n=)

110 mg Dabi

(6015)

150 mg Dabi

(6076)

Warfarin

(6022)

P=value

D/C at 1 yr (%) 14.5 15.5 10.2

Primary outcome –

Stroke/TE (%/yr)

1.53 1.11* 1.69 *<0.001

MI (%/yr) 0.72 0.74 0.53* <0.48

Intracranial Bleed 27 (0.23)* 36 (0.30)* 87 (0.74) <0.001

Extracranial bleed 299 (2.51) 342 (2.84) 315 (2.67) NS

GI Bleed 133 (1.12) 182 (1.51)* 120 (1.02) *<0.001

Life-threatening

Bleed

145 (1.220)* 175(1.45)** 212(1.8) *<0.001 and

**<0.04

No information on how these bleeds were managed!

Connolly NEJM 2009

ROCKET-AF

Outcome Rivaraxoban (20 mg OD)

Warfarin P value

Primary outcome

(Stroke/TE) %/yr

1.7 2.2 <0.001

Major bleeding %/yr 3.6 3.4 NS

ICH 0.5 0.7 0.02

GI Bleed 3.2 2.2 0.001

Hb ↓ >2 g 2.8 2.3 0.02

RBC Tx 1.6 1.3 0.04

Critical bleeding 0.8 1.2 0.007

Fatal bleeding 0.2 0.5 0.02

No information on how these bleeds were managed!

Patel NEJM 2011

ARISTOTLE

Outcome Apixaban (5 mg bid)

Warfarin P value

Primary outcome

(Stroke/TE) %/yr

1.27 1.60 <0.01

Major bleeding %/yr 3.6 3.4 NS

ICH 0.33 0.8 <0.001

GI Bleed 0.76 0.86 NS

Major or clinically relevant

non-major bleeding

4.07 6.01 <0.001

Any bleeding 18.1 25.8 <0.001

Net clinical outcomes –

stroke, TE, or major bleed

3.17 4.11 <0.001

Granger NEJM 2011

FDA approved TSOAs – but never

asked

How bleeds with TSOAs were managed?

How to detect drug levels if needed?

What is the therapeutic level?

Is there a reversal agent for urgent

surgery or serious bleeding?

Is patient’s weight important?

Assessment of compliance?

FDA

Warfarin Dabigatran Rivaroxaban Apixaban

Onset of action 2-5 days 0.5-2 hrs 1-4 hrs 3-4 hrs

Dosing Once a day Twice a day Once a day Twice a day

Bioavailability

(%)

90 4-10 60-80 50%

Prodrug No Yes No No

Variability Common Uncommon Uncommon Unknown

Therapeutic

Index

Narrow Not known Not known Not known

Diet/ drugs ++++ + Not known +

Monitoring

needed

Yes No No No

Test to monitor INR ?? ?Anti-Xa

assay

?Anti-Xa

assay

Elimination half

life

20-60 h 12-17 hrs 6-9 hrs 12 hrs

Renal Excretion Liver 85% renal 33% renal 25% urine

Antidote PCC/FFP/Vit K None None None

How to Manage Bleeding?

Hemostasis and Thrombosis

Research Society (HTRS)

Discontinue the drug

Supportive care

Activated charcoal for dabigatran

Dialysis or PLEX

PCC – either 3 or 4 factor non-

activated may be used

Did not recommend rFVIIa or plasma

Kaatz et al, AJH 2012

Removal of Drugs

Dabigatran Rivaroxaban Apixaban

Within 2-3 hrs Activated

charcoal

? ?

Dialysis 65% free – yes 65% Bound – No 87% bound–No

PLEX No Yes Yes

Line placement Problem Problem Problem

PLEX = Plasma exchange

Experimental Reversal of TSOAs

Prothrombin Complex Concentrate (PCC)

3 factor PCCs = Bebulin, Profilnine

4 factor PCC = Kcentra

Activated PCC = FEIBA

rFVIIa

Variable efficacy in controlling bleeding after

rat tail clipping, head trauma, etc

Ex vivo studies in human volunteers

rVIIa less effective than PCCs

Anticoagulants, Clinics in Lab Med Sep 2014

Rationale for PCC Use

Prothrombin gene mutation - increased levels of FII or prolongs t/2 With thrombophilia have levels >125%

Probably generates more thrombin

PCC - 50U/kg will increase FII and X significantly Generate more IIa – neutralize DTI

Generate more Xa – neutralize DXaI

Coagulation factors get activated in-vivo in minutes hence avoid aPCC

Ostermann et al. Thromb Haemost 2007; 98: 790–7

Time

144 96 72 48 24 18 12 6 2 60 30 10 5 Pre

Minutes: Post-Infusion Hours: Post-Infusion

100

200

300

50

100

150

200

200

200

150

100

50

250

150

100

FVII

FI

I FI

X (

%)

FX

Beriplex

15

Mean infusion 200IU/min; Mean dose 3750 IU (150 mL)

PK Healthy Volunteer Study 1001

Factor Levels Over Time

rFVIIa PCC

Scheduled Surgeries

Discontinue 24 hrs before

48 hrs before for procedures with high

risk for bleeding

Longer for patients with compromised

renal function

TT should be normal before surgery for

dabigatran

PT should be normal with no detectable

anti FXa activity for direct FXa inhibitors

Bleeding Management at UTSW

Hospitals

Tests to assess TSOAs effects

TT or PTT if normal – no DTI

anti-Xa assay (LMWH or Rivaroxaban assay)

Hemostatic strategy

STOP the drug

Topical hemostatic agents for epistaxis

PCC (KCentra) = 4000 Units (fixed dose)

Check above tests 30 min later

Assess clinical effect – may repeat PCC

22

TSOAs

vs

VKA

Newer Antiplatelet Drugs

Nature Review Cardiology 2014

Nature Review Cardiology 2014

Oral APAs

MOA = mechanism of action; P2Y12 = ADP receptor;

Features ASA Ticlopidine Clopidogrel Prasugrel Ticagrelor

MOA COX-1 P2Y12 P2Y12 P2Y12 P2Y12

Prodrug No Yes Yes Yes NO

Onset of action Minutes 4-7 days <24 hr <24 hr faster

Steady state of inhibition Hours 8-11 days 3-7 days 3-5 days Hours

Half-line (hr) 0.5 12.5 7-8 7 8-12

Reversible (days) 3-5 7 5 5-9 5

Bleeding risk + ++ ++ +++ ++++

PLT Tx for Urgent surgery No 1 dose 1 dose 1 dose No

PLT Tx for Urgent Eye/Neurosurgery or ICH

One dose Two doses Two dose Two doses Two doses

Elective surgery No wait 7 days 5 days 5 days 5 days

PLT Function Testing for APAs

AA = arachidonic acid; ADP = adenosine diphosphate; ASA = aspirin; Coll = collagen; CT = closure time; EPI = epinephrine; LTA = light transmission aggregometry; N = normal; ND = not done; PFA-100TM = PLT function analyzer; WBA = whole blood aggregation.

Agonists PF-100 TM CT (sec)

WBA/ VerifyNow

LTA Interpretation

EPI >200 ND ↓↓ ASA Effect

ADP N ↓↓↓ ↓ Clopidogrel

↓↓↓ ↓ Ticlopidine

↓↓↓ ↓ Prasugrel

↓↓↓ ↓ Ticagrelor

ADP N N N P2Y12 resistant

AA ND 0/↓ ↓/↓↓ ASA effect

AA ND N N ASA resistant

Vorapaxar (Zontivity)

Selective potent PAR-1 inhibitor that

blocks thrombin-mediated platelet

activation without interfering with

thrombin action on fibrinogen.

Rapidly absorbed with high bio-

availability

VERY long half-life of ~311 h (13 days)

Metabolized by CYP3A4 in the liver.

Significant Bleeding Complications

TRACER trial120 : NSTE-ACS were randomly assigned to

receive either vorapaxar (40mg loading dose and a 2.5 mg

daily maintenance dose) or placebo in addition to APA

therapy.

A significant 35% increase in mod/severe bleeding (7.2%

versus 5.2%; P<0.001) and three fold increase in ICH (1.1%

versus 0.2%; P<0.001) – terminated early.

TRA 2P-TIMI 50 trial - secondary prevention of ischemic

events in patients with known atherothrombotic disease (MI,

ischaemic stroke, PAD)

Ischemic benefit was hampered by a significantly increased

Mod/severe bleeding (4.2% versus 2.5%; P=0.001) and a two

fold increase in ICH (1.0% versus 0.5%; P<0.001) –

terminated early

FDA Approved in May 2014

For clinical use at 2.5mg once daily for the

reduction of thrombotic cardiovascular events in

patients with a history of MI or PAD

It must be used in addition to standard-of-care

antiplatelet therapy because no studies have

investigated vorapaxar monotherapy.

• Higher bleeding risk!

Vorapaxar is contraindicated in patients with a

history of stroke, transient ischemic attack, or ICH

and in those with active pathological bleeding

How to manage severe bleeding?

• rFVIIa

Pharmacologic Agents for Reversing

Effects of Antiplatelet Drugs

rFVIIa

DDAVP

In vitro Thrombin Generation by

rFVIIa

ASA and plavix treated platelets

Studied various does of rFVIIa and standard conc. of AA, ADP and Collagen

Measured Lag Time, peak and total thrombin generation

rFVIIa in 10, 20, 104 and 200 µg/Kg corrected TG in absence of TF

This effect can be important in pts on APA undergoing urgent surgery or bleeding

Recommendation 15-20 µg/Kg

Altman et al, JTH 2006

DDAVP for ASA Treated Patients

VWF release

Elective Cholecystecomy pts

Randomized to get ASA or ASA+DDAVP and control group

Pre-op BT 7.4’ in ASA vs 5.0’ in control

Post-DDAVP BT 5.5’

4/6 in ASA required blood; 5/6 had post-op bleeding episodes

None in DDAVP group

Recommendation: 0.3 µg/Kg IV

Flordal and Sahlin BJS 1993

Take Home Messages

TSOAs related bleeds Stop the drug

50 U/kg PCC

Antiplatelet therapy related bleed Stop the drug

P2Y12 antagonists

2 doses of PLT Jehovah's witness

rFVIIa 20µg/kg

DDAVP 0.3 µg/kg infusion

New Agents are going to kick…….