anticoagulant update - american college of physicians

1

Update on Anticoagulants

Jay Gaddy, MD, PhD

Indiana Hemophilia & Thrombosis Center

Indianapolis, Indiana

Disclosures

• None

Overview

• General discussion of anticoagulants

• New oral anticoagulants (NOACs) and their

targets

• Oral direct thrombin inhibitor - Dabigatran

• Oral factor Xa Inhibitors – Rivaroxaban,

Apixaban

• Reversal of anticoagulants

The ‘Ideal’ Oral Anticoagulant

• Good bioavailability

• No food or drug interactions

• Rapid onset of action

• Wide therapeutic window

• Predictable anticoagulant response

• Available antidote

• No unexpected toxicities

• Reasonable cost

• Mechanism to ensure compliance with therapy

Bauer, KA. Hematology, 2006:1;250

Warfarin

• When warfarin therapy is started, its anticoagulant

effects may not be apparent for several days.

• The duration of action of a single dose is 2–5 days.

• The therapeutic effect of warfarin exists within a

narrow therapeutic window as dictated by the INR.

• Considerable inter- and intra-individual dose

variability may be affected by a wide range of

physiologic (liver and thyroid function), genetic, and

environmental (eg, diet, other drugs) factors.

• Regular monitoring is required to avoid excessive or

insufficient anticoagulation.

Turpie, A. G.G. Eur Heart J 2008 29:155-165

Warfarin’s Therapeutic Window in A-fib

2

Spencer, F. A. et al. Arch Intern Med 2008;168:425-430.

Cumulative Incidence Rates of Bleeding in VTE Patients on Anticoagulation in the ‘Real World’ Limitations of Warfarin Therapy

Limitations Consequence

Slow onset of actions Overlap with parenteral anticoagulant

Genetic variation in

metabolism

Variable dose requirement

Multiple food & drug

interactions

Frequent INR monitoring

Narrow therapeutic index Frequent INR monitoring

Sub-class Drugs

Thrombin inhibitors UFH

Bivalirudin, Lepirudin**, Argatroban

Dabigatran

Xa-inhibitor UFH

LMWH

Fondaparinux

Rivaroxaban

Apixaban

(Edoxaban)

Vit K antagonists Warfarin

Most Common Currently Available Anticoagulants Generic and Brand Names

• Dabigatran – Pradaxa®

• Rivaroxaban – Xarelto®

• Apixaban – Eliquis®

Use of Newer Oral Anticoagulants

• Advantages:

• Fixed oral dosing

• No need to monitor anticoagulant effect with labs

• Fewer drug interactions (but there still are

some!)

• No dietary restrictions

Use of Newer Oral Anticoagulants

• Disadvantages:

• Lack of validated tests of anticoagulant effect

• No clinically proven antidotes

• More difficult to assess patient compliance

• Lack of data on long-term adverse events

• Absence of head-to-head comparisons between

novel oral anticoagulants

3

Targeting Specific Coagulation Factors

• Newer oral anticoagulants target specific points

in the coagulation cascade:

• Factor Xa inhibitors (eg, rivaroxaban, apixaban) target

factor Xa, preventing the conversion of prothrombin to

thrombin.

• Direct thrombin inhibitors (eg, dabigatran, ximelagatran)

target thrombin (factor IIa), blocking the conversion of

fibrinogen to fibrin.

• The goal of novel oral anticoagulants is to offer

more specific targeting and to afford more

predictable responses than current

anticoagulant therapies offer.

Targets of New Oral Anticoagulants Comparison of New Oral Agents

Feature

Dabigatran etexilate

Rivaroxaban Apixaban

Target Thrombin Factor Xa Factor Xa

Prodrug Yes No No

Dosing Fixed, 1-2x daily Fixed, once daily Fixed, twice daily

Bioavailability (%) 6 80 50

Time to onset (hrs) 2 2-4 1-3

Coagulation monitoring No No No

Half-life (h) 12–17 9-13 8-15

Renal clearance (%) 80 65 25

Interactions

P-gp inhibitors*

H2 blockers, PPIs

Combined P-gp and CYP3A4 inhibitors†

Combined P-gp and CYP3A4 inhibitors†

USA approved indications

A-fib VTE prevention and

treatment, A-fib A-fib

Weitz, Thrombosis and Haemostasis, 1/2010

Phase III Randomized Controlled Trials for VTE

Prevention

Drug Hip Arthroplasty Knee Arthroplasty Medical Surgical

Dabigatran RE-NOVATE RE-MODEL ... ...

RE-NOVATEII RE-MOBILIZE

Rivaroxaban RECORD1 RECORD3 MAGELLAN ...

RECORD2 RECORD4

Apixaban ADVANCE3 ADVANCE1 ADOPT ...

ADVANCE2

Eikelboom et al Circulation 2010 (121(1))

Phase III Randomized Controlled Trials non-VTE

prophylaxis

Anticoagulant VTE Treatment ACS AF

Idrabiotaparinux CASSIOPEA ... BOREALIS-AF

Dabigatran RE-COVER I RE-LY

RE-COVER II RELY-ABLE

RE-MEDY

RE-SONATE

Rivaroxaban EINSTEIN-DVT ATLAS JapaneseAF

EINSTEIN-PE ROCKET-AF

EINSTEIN-Extension

Apixaban Apixaban VTE APPRAISE2 AVERROES

Apixaban VTE extension ARISTOTLE

Edoxaban Hokusai-DVT ... ENGAGEAF TIMI48

Eikelboom et al Circulation 2010 (121(1))

4

FDA Approvals

• Dabigatran

• CVA and systemic embolism prevention in non-valvular A-fib

• Rivaroxaban


• VTE prevention in TKR and THR

• Treatment of VTE/PE

• Apixaban


Pradaxa® (dabigatran etexilate). Summary of product characteristics. Apr 2008


• Oral prodrug, converted to Dabigatran

• Binds clot-bound and free thrombin

with high affinity and specificity

• Bioavailability: 6.5%

• Renal excretion: 80%

• Half-life: 12–17 hours

• No interaction with food



• No participation with CYP450

• Predictable anticoagulant effect – no need for

monitoring

• No liver toxicity based on available clinical data

• Dyspepsia is a side effect

• PPIs and H2 blockers may affect absorption

• Potential medication interactions with P-gp affecting

drugs – Amiodarone, Dronedarone, Quinidine, Verapamil,

Ketoconazole, Rifampin, St Johns Wort


Dabigatran

● Other considerations

– Hygroscopic

Capsules should not be removed from original

container except for immediate use

Capsules only approved for 60 days after opening

bottle

Capsule should not be placed in pill boxes

Cannot crush or open pills for use in feeding tubes

Dabigatran: FDA Approval

• RE-LY (stroke prevention in patients with A-fib)

• 18,113 patients

• Dabigatran 110 and 150 mg bid compared with warfarin

• Treatment duration up to 3 years, median follow-up of 2 yrs

• 110 mg associated with rates of stroke or systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage

• Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke or systemic embolism but similar rates of major hemorrhage

Connolly, New England Jl Med, 2009

RE-LY: Major Bleeding & ICH

Dabigatran

Warfarin Dabigatran 110 mg vs warfarin

Dabigatran 150 mg vs warfarin

Dabigatran 150 mg vs 110 mg

110 mg 150 mg

Rate/

year

Rate/

year

Rate/

year

RR

(95% CI)

P RR

(95% CI)

P RR

(95% CI)

P

Major bleeding

2.7 % 3.1 % 3.4 % 0.80

(0.69-0.93) .003

0.93

(0.81-1.07) .31

1.16

(1.00-1.34) .052

All ICH 0.2 % 0.3 % 0.7 % 0.31

(0.20-0.47) < .001

0.40

(0.27-0.60) < .001

1.32

(0.82-2.17) .28

Connolly SJ. et al. N Engl J Med. 2009 Sep 17;361(12):1139-51.

5

RE-LY: Sites of Major Bleeding

Dabigatran Warfarin Dabigatran 110mg

vs Warfarin Dabigatran 150mg vs.

Warfarin

110mg 150mg

Annual

rate

RR

95% CI P

RR

95% CI P

Annual

rate

Annual

rate

Intracranial

0.23 % 0.30 % 0.74 % 0.31

0.20-0.47 < .001

0.40

0.27-0.60 < .001

Major Bleed 2.71 % 3.11 % 3.36% 0.80

0.69-0.93 .003

0.93

0.81-1.07 .31

Gastro-intestinal

1.12% 1.51 % 1.02% 1.10

0.86-1.41 .43

1.50

1.19-1.89 < .001

Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

RE-LY: GI Major Bleeding & MI

Dabigatran

Warfarin Dabigatran 110 mg vs warfarin

Dabigatran 150 mg vs warfarin

Dabigatran 150 mg vs 110 mg 110 mg 150 mg

Rate/

Year

Rate/

Year

Rate/

Year

RR

(95% CI) P

RR

(95% CI) P

RR

(95% CI) P

GI Major Bleed

1.1 % 1.5 % 1.0 % 1.10

(0.86-1.41) .43

1.50

(1.19-1.89) <.001

1.36

(1.09-1.70) .007

MI 0.72% 0.74% 0.53% 1.35

(0.98-1.87) .07

1.38

(1.00-1.91) .048

1.02

(0.76-1.38) .88

Connolly SJ. et al. N Engl J Med. 2009 Sep 17;361(12):1139-51.

RE-LY: Drug Discontinuation

Variable

Dabigatran 110 mg

(n = 6015)

Dabigatran 150 mg

(n = 6076) Warfarin (n = 6022) P-value a

Discontinued at 1 year, % 15% 16% 10% < .001

Discontinued at 2 years, % 21% 21% 17% < .001

a. Rates of discontinuation at 1 and 2 years were higher with dabigatran than with warfarin (P < .001). Rates are based on Kaplan-Meier estimates

Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

Dabigatran: Dosing in US

• CrCl > 30 – 150mg bid

• CrCl 15-30 – 75mg bid

• CrCl < 15 – not recommended

• CrCl should be assessed yearly in patients > 75


Rivaroxaban

• Predictable pharmacology

• High bioavailability

• Fixed dose

• No requirement for monitoring

• Inhibits free and thrombus associated Xa

• Contraindicated in severe renal insufficiency

• Drug interactions with meds that affect P-gp

and CYP3A4 – Ketoconazole, Rifampin,

Clarithromycin, St Johns Wort and HIV-protease

inhibitors (ritonavir)

Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005

Rivaroxaban

• Specific, competitive, direct FXa inhibitor

• Inhibits free and clot-associated FXa activity, and prothrombinase activity

• Inhibits thrombin generation via inhibition of FXa activity

• Prolongs time to thrombin generation

• Inhibits peak thrombin generation

• Reduces the total amount of thrombin generated

• Does not require a cofactor

Perzborn et al. J Thromb Haemost 2005; ICT 2004; Depasse et al. ISTH 2005; Kubitza et al. Clin Pharmacol Ther 2005; Br J Clin Pharmacol, 2007;

Graff et al. Turpie A. Oral Anticoagulation, a look to the future. Presentaiton. Hamilton, CA

Rivaroxaban (nM)

0.01 0.1 1 10 100 1000

Inh

ibit

ion

of

Fa

cto

r X

a a

ctiv

ity (

%)

0

20

40

60

80

100

Free FXa

Prothrombinase activity

Clot-associated FXa

6

Rivaroxaban: FDA Approvals

• VTE prevention following TKR and THR • RECORD studies

• Stroke prevention in non-valvular A-fib • ROCKET-AF studies

• Treatment of DVT and PE • EINSTEIN-DVT and EINSTEIN-PE studies

Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005

Phase III RECORD - VTE prevention

• Oral rivaroxaban 10 mg qd compared with subcutaneous enoxaparin

Study Duration of

rivaroxaban therapy

Duration of enoxaparin

therapy

RECORD1 THR 5 weeks 5 weeks

RECORD2 THR 5 weeks 10–14 days, followed by

placebo

RECORD3 TKR 10–14 days 10–14 days

RECORD4 TKR 10–14 days 10–14 days

RECORD - Efficacy endpoints

Primary

• Total venous thromboembolism (VTE): any deep vein

thrombosis (DVT, judged by venography), non-fatal

pulmonary embolism (PE), and all-cause mortality

Secondary

• Major VTE: proximal DVT, non-fatal PE, and

VTE-related death

• DVT: any, proximal, distal

• Symptomatic VTE

All endpoints were adjudicated centrally by independent, blinded committees

RECORD - Safety endpoints Main

• Major bleeding starting after the first blinded dose and

≤2 days after last dose

• Bleeding that was fatal, into a critical organ or required re-

operation

• Extra-surgical-site bleeding associated with a drop in

hemoglobin ≥2 g/dL or requiring transfusion of ≥2 units blood

Other • Any bleeding on treatment* • Non-major bleeding* • Hemorrhagic wound complications* • Cardiovascular adverse events • Liver enzyme levels

All endpoints were adjudicated centrally by independent, blinded committees

*Up to 2 days after last dose of study medication

Phase III outcomes in Rivaroxaban VTE prophylaxis

Rivaroxaban Enoxaparin P-values

(10 mg qd) (40mg qd or 30mg bid)

% (n/N) % (n/N)

RECORD1 (THR) 40mg qd

Total VTE 1.1 (18/1,595) 3.7 (58/1,558) <0.001

Major VTE 0.2 (4/1,686) 2.0 (33/1,678) <0.001

Major bleeding 0.3 (6/2,209) 0.1 (2/2,224) 0.18

RECORD2 (THR) 40mg qd

Total VTE 2.0 (17/864) 9.3 (81/869) <0.0001

Major VTE 0.6 (6/961) 5.1 (49/962) <0.0001

Major bleeding 0.1 (1/1,228) 0.1 (1/1,229) -

RECORD3 (TKR) 40mg qd

Total VTE 9.6 (79/824) 18.9 (166/878) <0.001

Major VTE 1.0 (9/908) 2.6 (24/925) 0.01

Major bleeding 0.6 (7/1,220) 0.5 (6/1,239) 0.77

RECORD4 (TKR) 30mg bid

Total VTE 6.9 (67/965) 10.1 (97/959) 0.012

Major VTE 1.2 (13/1,122) 2.0 (22/1,112) 0.124

Major bleeding 0.7 (10/1,526) 0.3 (4/1,508) 0.11

Weitz, Thrombosis and Haemostasis, Jan. 2010

Conclusions

• Rivaroxaban at a dose 10mg po qd shows

efficacy and tolerable side effects for VTE

prophylaxis

7

Rivaroxaban 20 mg daily

(15 mg for Cr Cl 30-49 ml/min)

Warfarin INR target: 2.5

(2.0-3.0 inclusive)

Primary Endpoint: Stroke or non-CNS Systemic Embolism

Atrial Fibrillation

Randomize Double Blind / Double Dummy

(N= 14,264)

Monthly Monitoring Adherence to standard of care guidelines

ROCKET AF: Study Design

a. Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

Risk Factors, at least 2 of: • CHF • Hypertension • Age 75 • Diabetes

OR • Stroke, TIA or systemic

embolus a

Data presented by Mahaffey, KW. AHA Scientific Sessions, Chicago, IL, November 2010

No. at risk:

Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634

Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655

ROCKET AF: Primary Efficacy Outcome Stroke and non-CNS Embolism

Event Rates are per 100 patient-years. Based on Protocol Compliant on Treatment Population

Warfarin

HR (95% CI): 0.79 (0.66, 0.96)

P-value Non-Inferiority: < .001

Days from Randomization

Cu

mu

lati

ve e

ven

t ra

te (%

)

Rivaroxaban

Rivaroxaban Warfarin

Event Rate

1.71 2.16

0

1

2

3

4

5

6

0 120 240 360 480 600 720 840 960


ROCKET AF: Time in Therapeutic Range

(TTR): INR Data

INR range

Warfarin

Median (25th, 75th)

< 1.5 2.7 (0.0 – 9.0)

1.5 to < 1.8 7.9 (3.5 – 14.0)

1.8 to < 2.0 9.1 (5.3 – 13.6)

2.0 to 3.0 57.8 (43.0 – 70.5)

> 3.0 to 3.2 4.0 (1.9 – 6.5)

> 3.2 to 5.0 7.9 (3.3 – 13.8)

> 5.0 0.0 (0.0 – 0.5)


ROCKET AF: Primary Safety Outcomes

Bleeding:

Rivaroxaban Warfarin HR 95% CI P-value Event Rate Event Rate

Major and non-major Clinically Relevant

14.91 14.52 1.03

0.96, 1.11 .442

Major 3.60 3.45 1.04

0.90, 1.20 .576

Non-major Clinically Relevant

11.80 11.37 1.04

0.96, 1.13 .345

Event Rates are per 100 patient-years Based on Safety on Treatment Population


Rivaroxaban Warfarin

HR (95% CI) P-value

Event Rate or N (Rate)

Event Rate or N (Rate)

Major 3.60 3.45 1.04 (0.90, 1.20) .576

≥ 2 g/dL Hgb drop 2.77 2.26 1.22 (1.03, 1.44) .019

Transfusion (> 2 units) 1.65 1.32 1.25 (1.01, 1.55) .044

Critical organ bleeding 0.82 1.18 0.69 (0.53, 0.91) .007

Bleeding causing death 0.24 0.48 0.50 (0.31, 0.79) .003

Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) .019

Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) .060

Intraventricular 2 (0.02) 4 (0.04)

Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) .051

Subarachnoid 4 (0.04) 1 (0.01)

Event Rates are per 100 patient-years Based on Safety on Treatment Population

ROCKET AF: Primary Safety Outcomes


ROCKET AF: conclusions

• Rivaroxaban demonstrated non-inferiority to Warfarin

for primary efficacy and safety outcomes: HR=0.79

(0.66-0.96), p<0.001; HR=1.03, (0.96-1.11), p=0.442,

respectively

8

Rivaroxaban: EINSTEIN

Studies – Phase III Trials

Open label, assessor blind, non-inferiority studies

comparing standard VKA anticoagulation to

Rivaroxaban for treatment of acute VTE and

prevention of recurrent VTE

• EINSTEIN–DVT – patients with objectively confirmed

proximal DVT

• EINSTEIN-PE – patients with objectively confirmed

pulmonary embolus

• Primary efficacy endpoint – Prevention of recurrent

symptomatic VTE

• Primary safety endpoint – Combination of major and non-major

clinically relevant bleeding

Rivaroxaban: EINSTEIN-DVT and

EINSTEIN-PE – Phase III Trials

EINSTEIN PE: study design

Randomized, open-label, event-driven, non-inferiority study

• Up to 48 hours’ heparinoid/fondaparinux treatment permitted before study entry

• 88 primary efficacy outcomes needed

• Non-inferiority margin: 2.0

Predefined treatment period of 3, 6, or 12 months

15 mg bid

Rivaroxaban

Day 1 Day 21

Enoxaparin bid for at least 5 days,

plus VKA INR 2.5 (range 2.0–3.0)

20 mg od N=4833

Rivaroxaban

R

Objectively confirmed PE ±

DVT

30-day post-study

treatment period

Primary efficacy outcome: first recurrent VTE

Principal safety outcome: first major or nonmajor clinically relevant bleeding

Rivaroxaban: EINSTEIN-DVT results

Rivaroxaban Warfarin Stats

Recurrent

symptomatic VTE 2.1% 3%

p < 0.0001 for

non-inferiority

Major and non-

major clinically

relevant bleeding

8.1% 8.1%

Composite of

primary efficacy

outcome and major

bleeding

2.9% 4.2% HR 0.67

All cause mortality 2.2 2.9% HR 0.67

Cardiovascular

events 0.7% 0.8% HR 0.79

EINSTEIN PE: primary efficacy Rivaroxaban

(N=2419)

Enoxaparin/VKA

(N=2413)

n (%) n (%)

First symptomatic recurrent VTE 50 (2.1) 44 (1.8)

Recurrent DVT 18 (0.7) 17 (0.7)

Recurrent DVT + PE 0 2 (<0.1)

Non-fatal PE 22 (0.9) 19 (0.8)

Fatal PE/unexplained death where PE cannot be ruled out

10 (0.4) 6 (0.2)

Rivaroxaban

superior

Rivaroxaban

non-inferior

Rivaroxaban

inferior

P=0.0026 for non-inferiority

(one-sided)

p=0.57 for superiority

(two-sided)

1.00 0 2.00

0.75 1.12 1.68*

*Potential relative risk increase <68.4%; absolute risk difference 0.24% (–0.5 to 1.02)

HR

EINSTEIN PE: principal safety outcome –

major or non-major clinically relevant bleeding

Rivaroxaban

n/N (%)

Enoxaparin/VKA

n/N (%)

HR (95% CI)

p-value

249/2412 (10.3) 274/2405

(11.4)

0.90 (0.76–1.07)

p=0.23

Safety population

0 30 60 90 120 150 180 210 240 270 300 330 360

15 14

10

13 12 11

9 8 7 6 5 4 3 2 1 0

Number of patients at risk

Rivaroxaban 2412 2183 2133 2024 1953 1913 1211 696 671 632 600 588 313

Enoxaparin/VKA 2405 2184 2115 1990 1923 1887 1092 687 660 620 589 574 251

Time to event (days)

Rivaroxaban

N=2412

Enoxaparin/VKA

N=2405

Cu

mu

lati

ve e

ven

t ra

te (

%)

9

Safety population

3.0

2.5

2.0

1.5

1.0

0.0

0.5

0 30 60 90 120 150 180 210 240 270 300 330 360

Cu

mu

lati

ve e

ven

t ra

te (

%)

Time to event (days)

Rivaroxaban

N=2412

Enoxaparin/VKA

N=2405

Number of patients at risk

Rivaroxaban 2412 2281 2248 2156 2091 2063 1317 761 735 700 669 659 350

Enoxaparin/VKA 2405 2270 2224 2116 2063 2036 1176 746 719 680 658 642 278

EINSTEIN PE: major bleeding

Rivaroxaban

n/N (%)

Enoxaparin/VKA

n/N (%)

HR (95% CI)

p-value

26/2412

(1.1)

52/2405

(2.2)

0.49 (0.31–0.79)

p=0.0032

EINSTEIN PE: conclusions

• In patients with acute symptomatic PE with or without

DVT, Rivaroxaban showed:

• Non-inferiority to LMWH/VKA for efficacy: HR=1.12 (0.75–

1.69);

pnon-inferiority =0.0026 for non-inferiority margin of 2.0

• Similar findings for principal safety outcome: HR=0.90

(0.76–1.07); p=0.23

• Superiority for major bleeding: HR=0.49 (0.31–0.79) p=0.0032

• Consistent efficacy and safety results irrespective of age, body

weight, gender, kidney function and cancer

• No evidence for liver toxicity

Rivaroxaban: Dosing in US

• A-fib

• 20mg daily with evening meal if CrCl >50

• 15mg daily with evening meal if CrCl 15-50

• DVT/PE

• 15mg bid with meals x 21 days followed by 20mg

daily with meal

• For patients with CrCl > 30

• Joint replacement surgery

• 10mg daily, 12 days for TKR, 35 days for THR

• For patients with CrCl > 30


Apixaban

• Predictable pharmacology

• High bioavailability

• Fixed dose

• No requirement for monitoring

• Inhibits free and thrombus associated Xa

• Contraindicated in severe renal insufficiency

• Drug interactions with meds that affect P-gp and

CYP3A4 – Ketoconazole, Rifampin, Clarithromycin, St

Johns Wort and HIV-protease inhibitors (ritonavir)

Apixaban: FDA Approval

• Stoke and thromboembolic prevention in non-

valvular AF

• ARISTOTLE and AVERROES Studies

10

ARISTOTLE: Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism

No. at Risk

Apixaban 9120 8726 8440 6051 3464 1754

Warfarin 9081 8620 8301 5972 3405 1768

21% RRR

P (non-inferiority)<0.001

Granger CB, et al. NEJM 2011;365:981-92

ARISTOTLE: Efficacy Outcomes


ARISTOTLE: Major bleeding

Apixaban 327 patients, 2.13% per year

Warfarin 462 patients, 3.09% per year

HR 0.69 (95% CI, 0.60–0.80); P<0.001

No. at Risk

Apixaban 9088 8103 7564 5365 3048 1515

Warfarin 9052 7910 7335 5196 2956 1491

31% RRR


Apixaban (N=9088)

Warfarin (N=9052)

HR (95% CI) P Value Event Rate

(%/yr) Event Rate

(%/yr)

Primary safety outcome: ISTH major bleeding*

2.13 3.09 0.69 (0.60, 0.80) <0.001

Intracranial 0.33 0.80 0.42 (0.30, 0.58) <0.001

Gastrointestinal 0.76 0.86 0.89 (0.70, 1.15) 0.37

Major or clinically relevant non-major bleeding

4.07 6.01 0.68 (0.61, 0.75) <0.001

GUSTO severe bleeding 0.52 1.13 0.46 (0.35, 0.60) <0.001

TIMI major bleeding 0.96 1.69 0.57 (0.46, 0.70) <0.001

Any bleeding 18.1 25.8 0.71 (0.68, 0.75) <0.001

ARISTOTLE: Bleeding outcomes


ARISTOTLE: Conclusions

• In patients with non-valvular a-fib, Apixaban

showed:

• Non-inferiority to VKA for efficacy: HR=0.79 (0.66-

0.95)

• Superiority for major bleeding: HR=0.69 (0.60-0.80)

p<0.001

• Superiority for reduction in all cause mortality:

HR=0.89 (0.89-0.998) p=0.046

Assesment of New Oral

Anticoagulants

• In general, they demonstrate equivalent or

superior efficacy and major bleeding safety

compared to recent standards of care

11

Comparison of New Oral

Anticoagulants

• **There are no head to head trials comparing

these agents. Trends that may suggest any

comparative superiority are only hypothesis

generating and need confirmation in head to head

trials

Comparable Efficacy of NOACs

in A-Fib

Copyright © The American College of Cardiology.

All rights reserved.

Comparable Major Bleeding

with NOACs in A-Fib

Copyright © The American College of Cardiology.

All rights reserved.

Time Warfarin in Therapeutic

Range (TTR)

● RE-LY (DABIGATRAN)

– 64% in Warfarin-experienced, 61% in Warfarin-naive

● ROCKET AF (RIVAROXABAN)

– Mean 55%, Median 58%

● ARISTOTLE (APIXABAN)

– Mean 62%, Median 66%

Testing of Hemostatic Function

● DABIGATRAN

– aPTT, thrombin clotting time (TCT) and ecarin cloting time

are prolonged

– TCT has a linear correlation with concentration but prolongs

quickly

– If TCT is not prolonged, Dabigatran level likely is low

● RIVAROXABAN

– Prothrombin time (PT) and anti-Xa affected

– Prothrombin time (PT) shows a linear dose response and is

prolonged to a similar extent as the degree of inhibition of

Xa (assay dependent)

Testing of Hemostatic Function

● APIXABAN

– Prothrombin time (PT) and anti-Xa affected

● Predictive ability of coag assays has not been clinically proven and

target drug levels have not been determined. trough levels may

not be detected.

● Anti-Xa activities can be measured against standard curves for

each Xa inhibitor but currently unsure what levels are consistent

with clinical efficacy or safety

12

Timing of last dose before surgery

CrCl (mL/min) Half-life (hrs) Low bleeding risk

Moderate or high bleeding risk

Dabigatran

> 80 13 (11-22) 24 hrs 2 days

> 50, < 80 15 (12-34) 24 hrs 2 days

> 30, < 50 18 (13-23) 2 days 4 days

< 30 27 (22-35) 4 days 6 days

Rivaroxaban

> 30 12 (11-13) 24 hrs 2 days

< 30 Unknown 2 days 4 days

Apixaban

> 30 - 24 hrs 2 days

Anticoagulation Interruption Before Surgery

Reversal of NOACs

● DABIGATRAN

– Gastric lavage or activated charcoal to reduce absorption

– Prothrombin complex concentrate (PCC) with efficacy in

some animal models, but no effect in reversing coagulation

assay abnormalities in human volunteers

– Recombinant activated factor VII (rFVIIa) did not reverse

coagulation assay abnormalities in human volunteers taking

Melagatran

– Acute hemodialysis (only 35% protein bound)

– **Antidote being developed – a humanized Fab fragment

that binds Dabigatran similarly to thrombin. Neutralizes

Dabigatran in animal model, does not bind thrombin

substrates or cause any coagulopathy or platelet clumping

Reversal of NOACs

● RIVAROXABAN

– Not dialyzable

– Four factor prothrombin complex concentrate (PCC) at 50

IU/kg reversed all coagulation assay abnormalities in a

human volunteer study

– Treat with PCC or activated factor VIIa

● APIXABAN

– Not dialyzable

– No data, but would treat as would for Rivaroxaban

Reversal of NOACs

● ** Anti-Xa antidote being developed.

– PRT064445 is a catalytically inactive, truncated form of

factor Xa. Reverses direct Xa inhibitors as well as LMWH

and Fondaparinux

● **Broad antidote for heparins, DTIs and direct

Xa inhibitors is being developed.

– PER977 is a small molecule that binds to and inhibits .the

above anticoagulants. Stable at room temp

Reversal of Warfarin: PCC vs FFP

– Retrospective cohort study

2006-2008 – FFP

2008-2010 – PCC (Octaplex, a 4 factor PCC)

– Adult patients with INR > 1.5

– Primary outcome was serious adverse events (death,

ischemic stroke, myocardial infarction, heart failure, venous

thromboembolism or peripheral arterial thromboembolism)

within 7 days

– Secondary outcomes included time to INR reversal, hospital

length of stay and red blood cells transfused within 48

hours

Hickey, M. et al. Circulation 2013

Reversal of Warfarin: PCC vs FFP

– 148 patients received FFP, 165 patients received Octaplex

– Serious adverse events

19.5% for FFP

9.7% for Octaplex (p=0.014, Relative Risk (RR) 2.0, 95% CI

1.1 to 3.5)

– Median INR reversal

11.8 hours for FFP

5.7 hours using Octaplex (p<0. 0001)

– Mean red cell transfusion

3.2 units for FFP

1.4 for Octaplex (p<0.0001).

Hickey, M. et al. Circulation 2013

13

Advantages of New Agents vs. VKAs

● RAPID ONSET OF ACTION

– May replace parenteral anticoagulants

for selected conditions

– Eliminates need for two anticoagulant

regimen (i.e. heparin and warfarin)

● PREDICTABLE THERAPEUTIC

EFFECT WITH FIXED OR WEIGHT-

BASED DOSING

– No routine coagulation monitoring

required

● LIMITED OR NO FOOD OR DRUG

INTERACTIONS

● SHORT HALF-LIFE

– Effect wears off more quickly than

VKAs

● NO NEED FOR BRIDGING AC FOR

INVASIVE PROCEDURES

Phillips et al. Jl Thromb Haem. 2010

● MORE CONVENIENT FOR PATIENT

– No routine monitoring, dietary limitations

and limited drug interactions

● MORE CONVENIENT FOR PHYSICIAN


● POTENTIAL FOR GREATER USE

– Barriers removed that limit more

widespread use

● MORE COST EFFECTIVE?


– Fewer adverse events

● POSSIBLE SUPERIOR EFFICACY

● POSSIBLE SUPERIOR SAFETY

Disadvantages of New Agents vs. VKAs

● NO ROUTINE COAGULATION MONITORING

– Cannot titrate dose

– Determination of failure of therapy vs. poor compliance

● SHORT HALF-LIFE

– Anticoagulation effect declines quickly if

compliance poor

– Poor compliance may affect efficacy more than with VKA

● NO CLINICALLY PROVEN ANTIDOTES

● NO MONITORING LAB MARKER AVAILABLE TO

RELIABLY MEASURE DRUG ACTIVITY IF NEEDED

● POTENTIAL DOSE ADJUSTMENT REQUIRED FOR

RENAL OR HEPATIC DYSFUNCTION

● COST?

Phillips et al. Jl Thromb Haem. 2010

Populations That Should be Initially Treated

with or Remain on Warfarin Rather Than be

Placed on a Newer Oral Anticoagulant

● ALREADY TAKING WARFARIN WITH EXCELLENT INR CONTROL

– RE-LY data demonstrated equivalent efficacy but increased GI bleeding

when comparing Dabigatgran 150mg bid to Warfarin with excellent control

● RENAL INSUFFICIENCY

– Consider if CrCl < 30 and definitely if < 15

● MECHANICAL HEART VALVES

● PREDISPOSITION TO GI BLEEDING

● POOR COMPLIANCE

– Concern regarding the quick loss of anticoagulant effect (question this)

● CAN’T AFFORD NEWER DRUG

Populations That Should Consider Treating

With Newer Oral Anticoagulants

● THOSE WITH UNEXPLAINED POOR INR CONTROL

– RE-LY data demonstrated equivalent efficacy but increased GI bleeding

when comparing Dabigatran 150mg bid to Warfarin with excellent control

● POOR INR CONTROL DUE TO UNAVOIDABLE DRUG INTERACTION

– Recurrent antibiotics, Amiodarone, Chemotherapy, APAP, Azathioprine,

polypharmacy

● NEW PATIENTS ON ANTICOAGULATION WITHOUT SIGNIFICANT

RENAL INSUFFICIENCY

● CAN AFFORD THE NEW DRUGS

Acknowledgments

• Gina Bryant

• Amy Shapiro, M.D.

• Chirag Amin, M.D.

anticoagulant update - american college of physicians

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