Download RE-MODEL

Advancements In
Anticoagulation
John Devlin, Pharm D
Feb 4, 2009
Agenda
1.
2.
3.
4.
Unmet needs in anticoagulation
Niche for new anticoagulants
Dabigatran Etexilate
Evidence for efficacy and safety from phase 3 randomized
trials
5. Implications for clinical practice
6. Comparing agents
7. Future developments
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
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”
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
Urgent Need to Replace
Warfarin!
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
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
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
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
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.
Aterial Thrombosis
Underuse of Warfarin in AF
AFASAK II
60
EAFT
SPAF II
SPINAF
SPAF III
Oral Anticoagulant
% on Medication
Aspirin
50
SPAF I
CAFA
40
30
BAATAF
AFASAK I
20
10
0
Visit Year
LASAF
PATAF
Japanese
NVAF study
New Oral Agents
New Oral Agents
Feature
Dabigatran Etexilate
Rivaroxaban
Apixiban
Target
Prodrug
Dosing
Bioavailability
Monitoring
Half-life (h)
Renal clearance
Interactions
Thrombin
Yes
Fixed, b.i.d.
6%
No
12-17
80%
P-gp inhibitor
Factor Xa
No
Fixed, b.i.d
50%
No
12
25%
Potent CYP3A4
inhibitors
Indications
Trials ongoing
VTE prevention
AF, ACS, VTE
treatment
Factor Xa
No
Fixed, o.d.
80%
No
5-9
65%
Combined P-gp
and CYP3A4
inhibitors
VTE prevention
AF, ACS, VTE
treatment
None
AF, ACS, VTE
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
Initiation
Phase
Contact
TF/ VII
XII
IX
XI
Amplification
Propagation
Phase
Thrombin
Activity
X
Platelet
Surface
VIII
Rivaroxaban
Apixaban
Xa
Common
Pathway
Dabigatran Etexilate
Thrombin
Fibrinogen
Fibrin
Anti-Xa or Anti-IIa?
Hirudin
Bivalirudin
Unfractionated
Argatroban
Heparin
Ximelagatran
Dabigatran Etexilate
Anti-IIa
Dalteparin
Enoxaparin
Nadroparin
Reviparin
Fondaparinux
Idraparinux
Rivaroxaban
Apixaban
Anti-Xa
Anti-Xa or Anti-IIa?
Pharmacologic Considerations
Anti-Xa
Anti-IIa
“Gatekeeper of the coagulation
cascade”
“Final Common Pathway”
Block thrombin generation
Block thrombin activity
Selective “targeted” effect
Block Contact Activation
Maintain -ve feedback
Block +ve feedback
Platelet Inhibition
Dabigitran Etixilate
The Molecule
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
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 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
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
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 Etixilate
&
Phase 3 Trials
REVOLUTION
Dabigatran Phase III Studies:
REVOLUTION
Enoxaparin
40 mg QD* OR
30 mg BID #
Start evening before surgery* OR
12-24 hours post-operatively#
R
Dabigatran etexilate
75 / 150 mg QD
Start 1-4 hours* OR
6-12 hours# post-operatively
Dabigatran etexilate
110 / 220 mg QD
Venography
Follow-up
Within 12 hours of last dose
12–14 weeks
*RE-MODEL and RE-NOVATE
#RE-MOBILIZE
Design:
Non-Inferiority in Modified
Intention-To-Treat Population
Study
Therapy
Duration
Enoxaparin
Dose (mg)
RE-MODEL
Knee
6-10 days
40 QD
RE-NOVATE
Hip
28-35 days
40 QD
Knee
12-15 days
30 BID
RE-MOBILIZE
Eriksson et al. J Thromb Haemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132
Methods - Procedures
Trial
RE-MODEL
RE-NOVATE
RE-MOBILIZE
Countries
Europe, Australia, South Africa
US , Canada, Mexico, UK
# Sites Sample Size
105
2101
115
3494
58
2615
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 Thromb Haemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132
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 Thromb Haemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132
Baseline characteristics
RE-MOBILIZE
RE-MODEL
RE-NOVATE
Patient Characteristics
Age (mean) - years
66
68
64
Females - %
58
66
56
Weight (mean) – kg
88
83
79
53
38
31
Time to first oral dose* (mean) – h
9.5
3.5
3.4
Treatment duration (median) – d
13
8
33
Anesthetic Details
General - %
Study Drug Administration
Primary Efficacy Outcome: Total VTE or All-Cause
Mortality
Enoxaparin
P=0.0003 for
non-inferiority
Dabigatran
P=0.017 for
non-inferiority
P=0.02 *
P<0.0001 for
non-inferiority
P<0.0001 for
non-inferiority
P=0.0009 *
RE-MODEL
† Confidence intervals not reported
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
Eriksson et al. J Thromb Haemost 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132; Eriksson et al. Lancet 2007
Safety Outcome: Major Bleeding Events
No significant differences between either dose of
dabigatran etexilate and enoxaparin.
Enoxaparin
Dabigatran
RE-MODEL
RE-MOBILIZE*
RE-NOVATE
* Confidence intervals not reported
Eriksson et al. J Thromb Haemost 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132; Eriksson et al. Lancet 2007
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
Total VTE Rate
(%)
P = 0.0005
(70/498)
Eriksson et al. J Thromb Haemost 2005
(121/539)
A post-hoc analysis from BISTRO II
(THR & TKR patients)
Meta-Analysis of RE-MODEL, RE-MOBILIZE, RENOVATE:
Total VTE & All-Cause Mortality
Dabigatran etexilate
Study or
220 mg QD
Enoxaparin
sub-category
n/N
n/N
RR [95% CI]
RR
RE-MOBILIZE
188/604
163/643
1.23 [1.03, 1.47]
RE-MODEL
183/503
193/512
0.97 [0.82, 1.13]
53/880
60/897
0.90 [0.63, 1.29]
RE-NOVATE
Total events: 424 (dabigatran etexilate), 416 (enoxaparin)
Test for heterogeneity: Chi2 = 4.73, df = 2 (P=0.09), I2 = 57.7%
Random Effects Analysis
Total (95% CI)
1987
1.05 [0.87, 1.26]
2052
Test for overall effect: Z = 0.47 (P = 0.64)
0.1 0.2
Analysis is based on the 220 mg
QD dose of dabigatran etexilate.
Wolowacz et al. Thromb Haemost 2009
0.5
Favours
Dabigatran Etexilate
1
2
5
10
Favours
Enoxaparin
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!
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
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
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?