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Advancements In Anticoagulation. John Devlin, Pharm D Feb 4, 2009 . Agenda. Unmet needs in anticoagulation Niche for new anticoagulants Dabigatran Etexilate Evidence for efficacy and safety from phase 3 randomized trials Implications for clinical practice Comparing agents

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Advancements In Anticoagulation


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advancements in anticoagulation

Advancements In Anticoagulation

John Devlin, Pharm D

Feb 4, 2009

agenda
Agenda

Unmet needs in anticoagulation

Niche for new anticoagulants

Dabigatran Etexilate

Evidence for efficacy and safety from phase 3 randomized trials

Implications for clinical practice

Comparing agents

Future developments

currently available anticoagulants
Currently available anticoagulants

Parenteral Agents

Heparins

UFH

LMWH (3 agents)

Heparinoids

Anti-Xa

Fondaparinux

DTIs

Bivalirudin / hirudin

Argatroban

  • Oral Agents
  • VKA’s
    • Warfarin
    • Acenocoumarol
place in therapy
Place in therapy

Venous thrombosis

  • Prevention
    • In-hospital
    • Out-of-hospital
  • Treatment
    • Initial
    • Long term

Arterial thrombosis

  • Treatment
    • ACS
  • Prevention
    • Stroke (AF, CHF, Prosthetic valves)
    • Post MI
    • PCI / HD
the magic bullet
The “Magic Bullet”

Oral Dosage Form

Little or no monitoring required

Equally efficacious and safe to current treatments

Consistent dosing regimen (wide therapeutic window)

Predictable PK and PD

Free from alcohol and food interactions

Free from drug interactions

Un phased by genetic factors (VKOR, CYP2C9)

Un phased by organ dysfunction

Reversibility

Rapid onset and offset

Inexpensive

where can we improve
Where Can We Improve?

Venous thrombosis

  • Prevention
    • In-hospital
    • Out-of-hospital
  • Treatment
    • Initial
    • Long term

Arterial thrombosis

  • Treatment
    • ACS
  • Prevention
    • Stroke (AF, CHF, Prothestic heart valves)
    • Post MI
    • PCI / HD
vte prevention call to action on dvt and pe
VTE Prevention“Call to Action” on DVT and PE

September 15, 2008 (Washington, DC) - The Office of the Surgeon General called today for a coordinated, multifaceted plan to reduce the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the us. The “call to action” is intended to increase awareness about these silent conditions and emphasize the importance of evidence based practices in the management of DVT.

out of hospital underuse of extended prophylaxis after major orthopedic surgery
Out of HospitalUnderuse of Extended Prophylaxis after major Orthopedic Surgery

ACCP guidelines for extended prophylaxis:

Hip fracture 1A

Hip arthroplasty 1A

Knee arthroplasty 2B

Reasons for underuse

Need for subcut injection

Need for monitoring and dose adjustment of VKA therapy

Coordinating drug coverage

vte prevention non traditional prophylaxis
VTE PreventionNon Traditional Prophylaxis

Medical patients (EXCLAIM trial)

4000 patients

6-14 days vs 1 month with LMWH

> 14 days?

Knee arthroscopy (KANT trial)

1800 patients

Nadroparin 3800 units vs elastic stockings for 7 days

0.9% vs 3.2 %

Thalidomide associated VTE

long term secondary vte prophylaxis
Long TermSecondary VTE Prophylaxis

Duration of anticoagulation for first unprovoked VTE

Proximal DVT or PE, no bleeding risk factors, and good monitoring is available

Those with permanent risk factors (ie Cancer)

Unprovoked VTE with strong preference for less frequent monitoring.

new oral agents1
New Oral Agents

Feature Dabigatran Etexilate Rivaroxaban Apixiban

Target Thrombin Factor Xa Factor Xa

Prodrug Yes No No

Dosing Fixed, b.i.d. Fixed, o.d. Fixed, b.i.d

Bioavailability 6% 80% 50%

Monitoring No No No

Half-life (h) 12-17 5-9 12

Renal clearance 80% 65% 25%

Interactions P-gp inhibitor Combined P-gp Potent CYP3A4

and CYP3A4 inhibitors inhibitors

Indications VTE prevention VTE prevention None

Trials ongoing AF, ACS, VTE AF, ACS, VTE AF, ACS, VTE

treatment treatment prevent/treat

Pradax Product Monograph 2008; Xarelto Product Monograph 2008; Turpie Eur Heart J 2008; Gross, Weitz. Arterioscler Thromb Vasc Biol 2008

new oral anticoagulant targets
New Oral Anticoagulant Targets

Initiation

Phase

TF/

VII

XII

IX

X

XI

Platelet

Surface

Amplification

Propagation

Phase

VIII

Rivaroxaban

Apixaban

Xa

Thrombin

Activity

Common

Pathway

Dabigatran Etexilate

Thrombin

Fibrinogen

Fibrin

anti xa or anti iia
Anti-Xa or Anti-IIa?

Hirudin

Bivalirudin

Argatroban

Ximelagatran

Dabigatran Etexilate

Fondaparinux

Idraparinux

Rivaroxaban

Apixaban

Dalteparin

Enoxaparin

Nadroparin

Reviparin

Unfractionated

Heparin

Anti-IIaAnti-Xa

key characteristics
Key Characteristics

Indicated for prevention of VTE post THR & TKR

Dose 110 mg 1-4 hours post surgery followed by 220 mg daily

dabigatran pharmacokinetics
Dabigatran Pharmacokinetics

Absorption

Oral Bioavailability: ~ 6.5%

Time to peak: 0.5-2 hours, delayed 2 hours by food

Distribution

Linear kinetics

~35% protein bound

Vd = 60-70L

dabigatran pharmacokinetics1
Dabigatran Pharmacokinetics

Metabolism

Hepatic glucuronidation to active metabolite

Elimination

Excreted in urine (85%, primarily as unchanged drug); fecal (6% of total dose)

t1/2 = 12-17 hours

drug interactions
Drug Interactions

Avoid concomitant use with p-glycoprotein inhibitors & inducers

Verapamil, Clarithromycin, *Quinidine

Rifampicin, St. Jonh’s Wort, Tenofovir)

Antacids

diminished clinical effect; avoid within 24 hours after surgery

Amiodarone

Adjust dosing to 150 mg daily dabigatran with amiodarone

Pantoprazole

Co-administration with Dabigatran may diminish clinical effect

special considerations
Special Considerations

Contraindications

Severe renal impairment (CrCl < 30 mL/min)

Concomitant treatment with strong P-Glycoprotein inhibitors (Quinidine)

Antidote

Switching agents

Special Patient Populations

Age

Pregnancy

Weight

End organ dysfunction

dabigatran phase iii studies revolution
Dabigatran Phase III Studies: REVOLUTION
  • Enoxaparin
    • 40 mg QD* OR
    • 30 mg BID #

Start evening before surgery* OR

12-24 hours post-operatively#

Dabigatranetexilate

75 / 150 mg QD

R

Start 1-4 hours* OR

6-12 hours# post-operatively

Dabigatranetexilate

110 / 220 mg QD

Follow-up

12–14 weeks

Venography

Within 12 hours of last dose

*RE-MODEL and RE-NOVATE

#RE-MOBILIZE

Design: Non-Inferiority in Modified Intention-To-Treat Population

Eriksson et al. J ThrombHaemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132

methods procedures
Methods - Procedures
  • Primary efficacy outcome:
      • Composite of total venous thromboembolic events (VTE) (symptomatic or venographic DVT and/or pulmonary embolism [PE]), and all-cause mortality during treatment
  • Secondary efficacy outcomes:
    • Composite of major VTE (proximal DVT and PE) and VTE-related mortality
    • Proximal DVT
    • Incidence of total VTE and all-cause mortality during follow-up
    • Individual components of the primary outcome

Eriksson et al. J ThrombHaemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132

methods procedures1
Methods - Procedures
  • Primary safety outcome:
    • Major bleeding events
      • Associated with ≥2 g/dL drop in haemoglobin or required transfusion of ≥2 units blood
      • Fatal, retroperitoneal, intracranial, intraocular, or intraspinal
      • Warranted treatment cessation or re-operation
    • Clinically relevant non-major bleeding events
    • Minor bleeding events
  • Events were classified by an independent, expert adjudication committee

Eriksson et al. J ThrombHaemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132

primary efficacy outcome total vte or all cause mortality
Primary Efficacy Outcome: Total VTE or All-Cause Mortality

Enoxaparin

P=0.0003 for

non-inferiority

P<0.0001 for non-inferiority

Dabigatran

P=0.017 for

non-inferiority

P<0.0001 for non-inferiority

P=0.02 *

P=0.0009 *

RE-MODEL

RE-MOBILIZE†

RE-NOVATE

(Hip)

(Knee)

* P-value that the margin of 9.2% as the upper limit of the 95% CI for ARD was exceeded

† Confidence intervals not reported

Eriksson et al. J ThrombHaemost 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132; Eriksson et al. Lancet 2007

safety outcome major bleeding events
Safety Outcome: Major Bleeding Events

Enoxaparin

No significant differences between either dose of dabigatran etexilate and enoxaparin.

Dabigatran

RE-MODEL

RE-MOBILIZE*

RE-NOVATE

* Confidence intervals not reported

Eriksson et al. J ThrombHaemost 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132; Eriksson et al. Lancet 2007

interpretational considerations
Interpretational Considerations

Failure to demonstrate non-inferiority of dabigatran in

Re-Mobilize

  • Factors that may have contributed
    • Higher dose of enoxaparin (30 mg BID vs 40 mg QD in RE-MODEL)
    • Comparator event rate was lower than anticipated (25.3% versus 37.7% in RE-MODEL)
    • Different median duration of treatment
    • Delayed initiation of dabigatran dosing
efficacy by timing of initiation of dabigatran
Efficacy by Timing of Initiation of Dabigatran

Total VTE Rate (%)

P = 0.0005

(70/498)

(121/539)

A post-hoc analysis from BISTRO II (THR & TKR patients)

Eriksson et al. J ThrombHaemost2005

meta analysis of re model re mobilize re novate total vte all cause mortality
Meta-Analysis of RE-MODEL, RE-MOBILIZE, RE-NOVATE: Total VTE & All-Cause Mortality

Dabigatranetexilate 220 mg QD

n/N

Enoxaparin

n/N

RR [95% CI]

RR

Study or sub-category

RE-MOBILIZE 188/604 163/643

RE-MODEL 183/503 193/512

RE-NOVATE 53/880 60/897

1.23 [1.03, 1.47]

0.97 [0.82, 1.13]

0.90 [0.63, 1.29]

Total events: 424 (dabigatranetexilate), 416 (enoxaparin)

Test for heterogeneity: Chi2 = 4.73, df = 2 (P=0.09), I2 = 57.7%

Random Effects Analysis

Total (95% CI) 1987 2052

Test for overall effect: Z = 0.47 (P = 0.64)

1.05 [0.87, 1.26]

0.1 0.2 0.5 1 2 5 10

Favours

DabigatranEtexilate

Favours

Enoxaparin

Analysis is based on the 220 mg QD dose of dabigatranetexilate.

Wolowaczet al. ThrombHaemost2009

the magic bullet1
The “Magic Bullet”…….

Oral Dosage Form

Little or no monitoring required

Equally efficacious and safe to current treatments

Consistent dosing regimen

Predictable PK and PD

Free from alcohol and food interactions

Free from drug interactions

Un phased by genetic factors (VKOR, CYP2C9)

Un phased by organ dysfunction

Reversibility

Rapid onset and offset

Inexpensive

not entirely yet much better
…..Not entirely yet much better!

Oral Dosage Form 

Little or no monitoring required 

Equally efficacious and safe to current treatments 

Consistent dosing regimen 

Predictable PK and PD 

Free from alcohol and food interactions 

Free from drug interactions X

Un phased by genetic factors (VKOR, CYP2C9) 

Un phased by organ dysfunction X

Reversibility X

Rapid onset and offset 

Inexpensive 

implications for clinical practice
Implications for Clinical Practice

Dabigatran etexilate is safe and effective for prevention of VTE in patients undergoing hip or knee arthroplasty

Potential to replace LMWH or fondaparinux

Major unmet need is out of hospital prophylaxis

Potential to improve guideline adherence and reduce VTE disease burden

summary
Summary

Massive unmet need for new oral anticoagulant

Dabigatran etexilate

Simple

Convenient, unmonitored

Safe

Effective

First in AF (September 2009)

Closing the care gap – more patients treated appropriately with improved quality of life.

Excellent replacement for warfarin

questions
Questions?

Questions?