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Emerging Anticoagulants for VTE Prevention and Treatment: Is change upon us?. Amanda C. Walker, PharmD Clinical Pharmacist University of Utah University Thrombosis Service. Objectives. Describe the pharmacology and mechanism of action for new and emerging anti-thrombotic agents

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emerging anticoagulants for vte prevention and treatment is change upon us

Emerging Anticoagulants for VTE Prevention and Treatment: Is change upon us?

Amanda C. Walker, PharmD

Clinical Pharmacist

University of Utah

University Thrombosis Service

objectives
Objectives
  • Describe the pharmacology and mechanism of action for new and emerging anti-thrombotic agents
  • Discuss and review current randomized controlled trials for new and emerging anti-thrombotic agents for VTE prevention and treatment
  • Evaluate the adverse drug reactions and side effects associated with these new agents
current limitations
Current Limitations

Lassen MR. Vasc Health Risk Manag. 2008;4(6):1373-86.

new and emerging anticoagulants
Anti – Xa : direct

Rivaroxaban (oral)

Apixaban (oral)

Betrixiban (oral)

Edoxaban (oral)

Otamixaban (parenteral)

LY – 517717 (oral)

DU – 176B (oral)

DX – 9065a (parenteral)

PRT054021 (oral)

Anti – Xa : indirect

Idraparinux biotinylated (parenteral)

Anti – IIa

Dabigatran (oral)

Odiparcil (oral)

Flovagatran (parenteral)

Pegmusirudin (parenteral)

Peg Hirudin

Desiruidin

New and Emerging Anticoagulants
site of action for new anti thrombotic agents

Indirect Xa

Inhibitors

“-parinux”

AT

Direct Thrombin Inhibitors

“-gatran”

warfarin

Site of Action for New Anti-thrombotic Agents

Extrinsic

XII

Intrinsic

XI

Tissue Factor

IX

VII

VIII

Direct Xa Inhibitors

“-xaban”

X

V

II

Fibrinogen

Fibrin Clot

factor xa vs factor iia
Factor Xa

One Xa forms many IIa

Limited role in diversity of action outside of coagulation cascade

Clinical effectiveness

Fondaparinux

Factor IIa

Supports feedback amplification through Factor V, Factor VIII, and Factor IX

Has many cellular effects

inflammation

Clinical effectiveness

Argatroban

Hirudins

Factor Xa vs. Factor IIa
direct factor xa inhibitors
Direct Factor Xa Inhibitors

XII

Intrinsic

Extrinsic

XI

TF

IX

VII

VIII

Direct Xa Inhibitors

“-xaban”

X

V

II

Fibrinogen

Fibrin Clot

apixaban
Oral tablet

Bioavailability: 50%

Peak Plasma Levels = 3 hrs

Half-life ~ 12 hours

Metabolized in liver via CYP3A4 and CYP independent mechanisms

Eliminated via multiple pathways

No laboratory monitoring required

Manufactured by Bristol-Myers Squibb/Pfizer

Plan to submit for U.S. approval in 2009-2010

Apixaban
apixaban efficacy outcomes in tkr phase ii
Apixaban Efficacy Outcomes in TKR (Phase II)

Incidence of VTE and all-cause death (%)

Duration = 10 -14 days

5

QDay

2.5

BID

10

QDay

5

BID

20

QDay

10

BID

Enox 30mg BID

(n=152)

Warf

(n=153)

Apixaban (mg) (n = 933)

Lassen MR, et al. J Thromb Haemost. 2007;5:2368 – 2375.

apixaban safety outcomes in tkr phase ii
Apixaban Safety Outcomes in TKR (Phase II)

Incidence of bleeding events (%)

5

QDay

2.5

BID

10

QDay

5

BID

20

QDay

10

BID

Enox 30mg BID

(n=152)

Warf

(n=153)

Apixaban (mg) (n = 933)

advance 1 results of efficacy vs enoxaparin 30 mg bid
ADVANCE – 1: Results of Efficacy vs. Enoxaparin 30 mg BID

RR: 1.02 (95% CI: 0.78 to 1.32) P=0.06 for non-inferiorityAbsolute Difference: 0.1% (95% CI: -2.22 to 2.44) P<0.001 for non-inferiority

8.99%N = 1157

8.85%N = 1130

Lassen MR, et al. NEJM 2009;361:594 – 604.

advance 2 primary efficacy results
ADVANCE – 2: Primary Efficacy Results

RR: 0.62; 95% CI: 0.51 – 0.74p<0.0001*

24.5%n = 997

15.1%n = 975

*Composite of adjudicated asymptomatic DVT by venography; objectively confirmed

symptomatic DVT or PE; or death from any cause. One-sided p-value for superiority.

summary of advance 2 study
Summary of ADVANCE – 2 Study
  • Apixaban 2.5mg BID vs. Enoxaparin 40mg QD
  • Superior for:
    • Primary endpoint of ANY DVT/PE/All-Cause Death
    • Secondary endpoint for Major VTE
  • Lower observed bleeding rates
    • Major
    • Clinically relevant non-major
  • Similar overall safety profile
rivaroxaban
Brand name Xarelto®, Bayer

Oral tablet

High oral bioavailability (>80%)

Onset of action 2-4 hours

Half-life 9-12 hours

No observed effects on agonist-induced platelet aggregation

Primarily renal elimination

No laboratory monitoring required

No dosage adjustment for gender, age, extreme body weight

Approved by Europe and Canadian agencies, and under FDA review currently

Rivaroxaban
rivaroxaban in vte prevention record 3 tka

RRR 49%

RRR 62%

Rivaroxaban in VTE Prevention:RECORD 3 - TKA

2531 patients

%

%

No Difference

rivaroxaban in vte prevention record 4 tka
Rivaroxaban in VTE Prevention:RECORD 4 - TKA

Rivarox: RRR 31%; ARR 3.2%

%

%

NotSignificant

Turpie, et al. Lancet 2009;373:1673 – 80.

rivaroxaban ongoing phase iii clinical trials
Rivaroxaban Ongoing Phase III Clinical Trials

DVT

Einstein-DVT

Rivarox 15mg BID x 3 wks then 20mg Qday vs Enox/VKA

PE

Einstein-PE

Rivarox 15mg BID x 3 wks then 20mg Qday vs Enox/VKA

DVT/PE

Einstein-Extension

Rivarox 20mg Qday vs Placebo

AF

Rivarox 20 mg Qday vs Warfarin

Medically Ill

Rivarox 10mg Qday x 35 days vs Enox 40mg Qday x 10 days

indirect factor xa inhibitors

Indirect Xa

Inhibitors

“-parinux”

AT

Indirect Factor Xa Inhibitors

XII

Intrinsic

Extrinsic

XI

TF

IX

VII

VIII

X

V

II

Fibrinogen

Fibrin Clot

idraparinux
Idraparinux
  • Once weekly SC injection
  • 100% SC bioavailability
  • Half-life ~ 96-130 hours
  • Renal elimination
  • No monitoring required
  • Manufactured by

Sanofi-Aventis

  • Plan to file for U.S. approval in 2009
van gogh trials
Van Gogh Trials

Idraparinux 2.5 mg SC qweek vs standard therapy (heparin/LMWH + VKA)

DVT Study

PE Study

VTE Extended Study

Idraparinux vs placebo

2904 patients

2215 patients

1215 patients

↔ 3- and 6-month

recurrence

↓ bleeding at 3 mo

↔ bleeding at 6 mo

↔ mortality

↑3- and 6-month

recurrence

↓ bleeding at 3 and

6 mo

↑ mortality

↓ recurrent events

↑ bleeding

↔ mortality

amadeus trial
Amadeus Trial

4576 patients

  • Non-valvular atrial fibrillation
  • Idraparinux 2.5 mg SC qweek vs VKA
  • Trial stopped early due to excess clinically relevant bleeding with idraparinux
slide23

Idraparinux Biotinylated

Idraparinux sodium

Idraparinux

Biotinylated

Avidin

Biotin arm with spacer

  • No pharmacological effect
  • IV injection
  • Short half-life (10-16 min)
phase iii clinical trials with idraparinux biotinylated

E Q U I N O X

C

SSIO

EA

Phase III Clinical Trials with Idraparinux Biotinylated

Idraparinux biotinylated 3 mg weekly vs warfarin in 6-month PE treatment (3200 patients)

Idraparinux biotinylated 3 mg weekly vs idraparinux 2.5 mg weekly in 6-month DVT tx (700 patients)

BOREALIS-AF

Idraparinux biotinylated 3 mg weekly vs warfarin in AF (9600 patients)

direct thrombin inhibitors

Direct Thrombin Inhibitors

“-gatran”

Direct Thrombin Inhibitors

XII

Intrinsic

Extrinsic

XI

TF

IX

VII

VIII

X

V

II

Fibrinogen

Fibrin Clot

slide26

COMPANY NEWS; F.D.A. PANEL VOTES AGAINST BACKING DRUG BY ASTRAZENECA

COMPANY NEWS; F.D.A. REJECTS ASTRAZENECA'S ANTI-CLOTTING DRUG

Published: September 11, 2004

Published: October 9, 2004

AstraZeneca failed to win backing from a federal government panel for its Exanta blood thinner, a possible first alternative to the drug Coumadin in more than 50 years.

AstraZeneca said yesterday that federal regulators did not approve its anti-clotting drug, Exanta.

dabigatran
No dietary/food interactions

Brand name Rendix™ or Pradaxa®, Boehringer-Ingelheim

Approved in Europe March 2008; plans are to obtain U.S. FDA approval by 2010

Oral capsule

Rapid onset of action

Half-life 12-17 hours

Renal elimination

No routine monitoring required

P-gp substrate—use with caution when administered concomitantly with P-gp inhibitors

Dabigatran
dabigatran in tkr re model phase ii

Dabigatran

Dabigatran in TKR:RE-MODEL (Phase II)

% Total VTE & Death

% Adverse Events

n=1541 patients treated 6-10 days, followed for 3 months post-surgery

Dabigatran

dabigatran in thr re novate phase ii

Dabigatran

Dabigatran

Dabigatran in THR:RE-NOVATE (Phase II)

% Total VTE & Mortality

% Adverse Events

n=2651 patients treated 28-35 days, followed for 3 months post-surgery

Eriksson BI et al. Lancet 2007;370:949-56.

summary
Summary

Time to Market for New Anti-Thrombotic Agents

Apixaban

Dabigatran

Otomaxiban

Idraparinuxbiotinylated

Rivaroxaban

2010

2011

2012

2013

potential limitations of new anticoagulants
Potential Limitations of New Anticoagulants
  • Antidotes
    • None of the newer agents has a specific antidote
  • Monitoring
  • Adverse Drug Events
  • Compliance
  • Cost
  • Clinical Trials vs. Actual Clinical Practice
  • Patient populations not even studied (i.e. Cancer)
conclusion
Conclusion
  • Several oral and parenteral Anti Xa and Anti IIa drugs are under development at this time
  • Rivaroxaban and Dabigatran are approved in the European Union and Canada for the prophylaxis of DVT and awaiting FDA review/approval
  • Safety issues are of prime importance in the development of these drugs and will be strongly scrutinized upon review
what about re ly
What about RE-LY?

Dabigatran versus Warfarin in Patients with Atrial Fibrillation

  • Non-inferiority trial
  • Over 18,000 patients
  • Followup = 2 years

Dabigatran 110 mg and 150mg

vs.

Adjusted dose warfarin