Download New Approaches to Chronic Anticoagulation

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March 24-27, 2007
New Orleans, LA
New Approaches to Chronic Anticoagulation:
Factor XA Inhibition
C. Michael Gibson, MS, MD
Associate Professor of Medicine
Harvard Medical School
Chief of Clinical Research
Cardiology Division
Beth Israel Deaconess Medical Center
Boston, MA
Meeting The Unmet
Needs in Chronic
Anticoagulation
C. Michael Gibson, M.D., M.S.
PCI Cure: Death / MI Remain High at One Year
Despite PCI & Dual Antiplatelet Therapy
Cumulative Hazard Rates Death / MI
<48 hrs after rand
0.20
Denotes median
Time to PCI
PCI ≥ 48 hrs from rand and
during initial hosp
0.20
PCI after hospital
discharge
0.20
ASA
ASA
0.15
0.15
0.10
0.10
0.05
0.05
ASA
0.15
0.10
ASA + Clopidogrel
ASA + Clopidogrel
0.05
ASA + Clopidogrel
RR:0.72 (0.51-1.01)
RR:0.53 (0.27-1.06)
0.0
0.0
0
100 200 300
Days of Follow-up
RR:0.70 (0.48-1.02)
0.0
0
100 200 300
Days of Follow-up
0
100 200 300
Days of Follow-up
Lewis BS, et al. Am Heart J. 2005;150:1177-1184.
Thrombus & Complex Lesion Remains One
Month After STEMI
% Thrombus on Angioscopy
100%
83%
80%
79%
70%
71%
60%
40%
20%
• Angioscopic findings
suggestive of plaque
instability are extremely
frequent (75% to 80% of
the study population) as
is the presence of clot
even in the absence of
clinical symptoms.
• Only 16% of clot seen
on angio
0%
< 8 Days
8<&
10 < &
> 15 Days
(n=18)
< 10 Days
< 15 Days
(n=14)
(n=10)
(n=14)
Days after lysis or medical therapy
Van Belle et al. Circulation. 1998;97:26-33.
Angioscopy Follow-up 6 Months After
SES or BMS Implantation
Grade 1
Thin neointima
P<.05
P=.63
P=.80
Stent Coverage Grade
2.5
2
1.5
Edge
*
*
Body
Overlapping
Segment
*
1
*P<.001 compared
with the corresponding
segment in the BMS.
0.5
0
Visible
Thrombus
P=.70
P<.001
P<.0005
Grade 2
Full neointima
n=21 n=33 n=12
SES
n=28 n=33 n=5
BMS
Frequency of Persistence
of Thrombus (%)
Grade 0
No neointima
100
>80%
80
60
P=.031
40
20
0
SES
BMS
(N=46, 66 lesions: 33 SES, 33 BMS)
Takano M, et al. Eur Heart J. 2006;27:2189-2195.
Recurrent MI Following Lysis For STEMI
25%
% Mortality 2 yrs
19.6%
20%
p<0.0001
15%
10.1%
10%
5%
n=19,265
n=836
0%
No Reinfarction
•Recurrent MI is
associated with a
doubling in
mortality at 2
years
•Patients at risk
cannot be
identified
clinically
Reinfarction
Gibson CM et al, JACC 2003
Incidence of LV Mural Thrombus in the Era
of Modern Reperfusion Therapy
• Series from 1997-2002
• Among first anterior
STEMI patients echoed
within 72 hours LV clot
was seen in 23.5%.
(36/153)
* STEMI pts managed with lytic or medical mgt
Porter A et al. Coron Artery Dis. 2005 Aug;16(5):275-9
Meta Analysis of Anticoagulation
Rates of Recurrent MI
Rothberg et al. Ann. Int. Med. 2005;143:241-250
ASPECT II: Coumadin is Efficacious in ACS, But
Discontinuation is Common
999 Pts within 8 wks of UA or Acute MI
Rx : ASA 80 mg; Coumadin (INR 3-4); or Combination: ( INR 2-2.5)+ ASA 80 mg
Efficacy
Safety
%
Death,MI,CVA
30
Major Bleed
Tranfusion
Minor Bleed
20
15
8
10
5
1 1
1 1
2 1
0
ASA
Rate of
Discontinuation
10%
Coumadin
Combo
19%
20%
van Es et al Lancet 360:109,2002
OASIS 2: Impact of Anticoagulation
Discontinuation
P=0.02
P=0.33
P=0.005
P=0.16
21.3
20
18.5
Std Rx
16.5
% Pts
Oral A/C + ASA
15
11.9
10
8.9
9
7.8
6.1
5
0
Compliance:
Good
(% on Oral AC)
>70 %
Bad
Good
Bad
< 70%
> 70%
< 70%
CVD,MI,CVA
CVD, MI, CVA, Rehosp UA
OASIS Inv JACC 37:475,2001
Anticoagulation Therapy
Agent
Disadvantages
Heparin
•
•
•
Parenteral administration
Risk of heparin-induced thrombocytopenia (HIT)
Narrow therapeutic window (low bioavailability, short halflife)
Warfarin
•
Requires frequent monitoring due to:
– Narrow therapeutic window
– Unpredictable pharmacology
– Multiple drug–drug and food–drug interactions
– Increased risk of major and minor bleeds
LMWH
•
•
Parenteral administration
Risk of heparin-induced thrombocytopenia (HIT)
Indirect Xa
Inhibitor
(e.g. fondaparinux)
•
•
•
Parenteral administration
Long half-life
Limitations related to special patient populations
Direct
Thrombin
Inhibitors
•
•
Parenteral administration
Current applications limited to cardiovascular
management
Albans S et al. Eur J Clin Invest 2005;35(Suppl 1):12-20.
Nadia Comaneci 1976: First Perfect Score of 10 In Olympics
Anticoagulation is like a
balance beam performance
Both efficacy and safety are
important, and if you fail to
balance efficacy and safety,
the patient may get hurt
The Search for an Anticoagulant
That Balances Safety and Efficacy
Thrombosis
Optimal Safety
and Efficacy
Bleeding
Dose (concentration) of Anticoagulant
Meeting the Unmet Need in Long Term
Anticoagulation in ACS
•Unmet anticoagulant needs:
• Safe
• Effective
• Ease of use
• One dose
• No monitoring
• Unaffected by diet
ESTEEM: Primary Endpoint
% Death/MI/Recurrent Ischemia
Death/MI/Severe Recurrent Ischemia
20%
16.3%
p=0.03
15%
12.7%
10%
•The primary
endpoint was lower
for pooled
ximelagatran
compared with
placebo (12.7% vs
16.3%, HR 0.76,
p=0.03)
•Ximelagatran Dc’d in
7% of pts due to LFT
abnormalities
5%
n=1,245
n=638
0%
Placebo
Pooled Ximelagatran
• Oral direct thrombin inhibitor (IIa), no coagulation monitoring
is required, fixed dose, eval in STEMI or non-STEMI
Rivaroxaban: An Oral Direct Xa Inhibitor
• Direct, specific, competitive Factor Xa inhibitor
• Inhibits free and fibrin-bound Factor Xa activity,
and prothrombinase activity
• Does not directly inhibit thrombin, but inhibits
thrombin generation via inhibition of Factor Xa activity
• Does not affect agonist-induced platelet aggregation,
and therefore has no direct effect on primary
hemostasis
• Does not require a cofactor
• No interaction with aspirin, enoxaparin, digoxin,
naproxen, ranitidine, or antacids
Perzborn et al., J Thromb Haemost 2005; ICT 2004; Depasse et al., ISTH 2005;
Kubitza et al., J Clin Pharmacol 200; ASH 2005; Fareed et al., ISTH 2005
Rivaroxaban: a Potent and Selective Oral
Direct Factor Xa Inhibitor
TF (Tissue Factor)
XIa
XI
Intrinsic Pathway
IX
IXa
VIIa + TF
VIIIa
X
If either the Intrinsic or Extrinsic
pathway is activated, Rivaroxaban
blocks the final common
coagulation pathway to form
thrombin by blocking Factor XA
VII
Extrinsic Pathway
Xa
Va
II
IIa (Thrombin)
Fibrinogen
Fibrin
Prothrombin Time Correlates Strongly with
Plasma Concentrations of Rivaroxaban
40
Prothrombin time (s)
Prothrombin time
Model
30
r = 0.958
20
10
0
0
100
200
300
400
500
Plasma concentration of Rivaroxaban (µg/l)
Kubitza et al. ASH 2003
600
Rivaroxaban: Persistent Antithrombotic
Effect Out to 24 Hours
% Inhibition of Factor Xa
70
Rivaroxaban 1.25 mg (n=8)
Rivaroxaban
5 mg (n=6)
Rivaroxaban
10 mg (n=8)
Rivaroxaban
20 mg (n=7)
Rivaroxaban
40 mg (n=8)
Rivaroxaban
80 mg (n=6)
Placebo (n=25)
60
Anti-Xa Activity
50
40
30
20
10
0
-10
0
2
4
6
8
10
12
14
16
18
20
Time (hours)
► All once-daily dosage regimens demonstrated
Xa inhibition for out to 24 hours
► These results provided foundation for selection of
once-daily dosing regimen for Phase III programs
Kubitza, et al. Clin Pharmacol Ther 2005;78(4):412-21.
22
24
Rivaroxaban: Human Pharmacokinetics
• Dose peaks in 2.5–4 hours, half life 5-9 hours (11-13
hours in elderly)
• One dose will be selected for clinical use
• No monitoring required given consistent dose
response
• Dual modes of excretion
•Renal (66%), but no excess bleeding associated
with CrCl to date
•Faecal/biliary (28%)
• Minimal drug/drug interactions, no major circulating
metabolites, no drug accumulation
Kubitza et al., Eur J Clin Pharmacol 2005; Eriksson et al., J Thromb Haemost 2006; Turpie et al., J Thromb
Haemost 2005; Kubitza et al., ISTH 2005; Kubitza et al., ASH 2005; Kubitza et al., J Clin Pharmacol 2006
Rivaroxaban: Anti-Thrombotic Efficacy
Thrombus reduction (%)
100
*P<0.05 ; **P<0.01
**
80
*
60
• Arterial thrombosis
rabbit arteriovenous
shunt model
• Rivaroxaban dosedependently prevented
arterial thrombosis
40
20
0
0.3
1.0
3.0
Rivaroxaban (mg/kg) p.o.
Rivaroxaban Safety: Bleeding Time
Tail Transection Bleeding Time in Rats
Compound
X-fold prolongation of
bleeding time at ED50
(control =1)
Rivaroxaban [po]
1.8
Enoxaparin
[sc]
2.2
Ximelagatran [po]
3.7
Dabigatran
[po]
4.9
Warfarin
[po]
> 6.3
 Bleeding time comparable to enoxaparin
 Lower compared to thrombin inhibitors or warfarin
Rivaroxaban: Bleeding Time with
Combination Therapy
Tail Transection Bleeding Time in Rats
Compounds
Clopidogrel 1 mg/kg [po]
Aspirin 3 mg/kg [po]
Clopidogrel 1 mg/kg [po]
Aspirin 3 mg/kg [po]
+
Rivaroxaban 0.1 mg/kg [iv]
X-fold prolongation
of bleeding time
2.1 +/- 0.3
2.5 +/- 1
Similiar Bleeding Times
Dose–response Relationship: Safety And
Efficacy
DVT, PE, and all-cause mortality
Major, post-operative bleeding
Incidence rate %
30
20
10
0
0
5
10
15
20
25
30
35
40
Enoxaparin
40 mg
Total daily dose (mg) of Rivaroxaban
Eriksson et al., Circulation 2006
Safety and Tolerability
• Rivaroxaban was well tolerated, with similar incidence of AEs as
enoxaparin
• Rivaroxaban did not affect ECG parameters
• Rivaroxaban did not have any substance-specific effects on
laboratory parameters (except for clotting tests)
• LFT increases with BAY 597939 did not exceed the level observed
with enoxaparin
– There was no dose-dependent increase in transaminase levels
Liver function
test (LFT)
ALT > 3× ULN
%
Rivaroxaban
Enox
5 mg
10 mg
20 mg
30 mg
40 mg
40 mg
5/119
4.2
6/133
4.5
4/133
3.0
7*/129
5.4
5/127
3.9
10/140
7.1
*One patient had ALT >3× ULN and bilirubin >2× ULN (occurring before first intake of study drug)
Safety
Rivaroxaban
Efficacy
Ease
CM Gibson 2007
Rivaroxaban: Conclusions
• Is a selective, reversible, active-site directed Factor Xa
inhibitor that inhibits coagulation triggered by both the
collagen (intrinsic) and tissue factor (extrinsic)
pathways
• Reduces thrombus formation in both venous and
arterial thrombosis models
• Has a bleeding risk comparable to Enoxaparin, and
lower compared to thrombin inhibitors and Warfarin, in
preclinical in vivo models
CM Gibson 2007
Rivaroxaban: Conclusions
• Reaches Peak (Cmax)) in 2.5–4 hours; half-life of 5–9
hours at steady state (little longer in older)
• Dual modes of excretion: Renal (66%) & Faecal / biliary
(28%)
• No substantial accumulation after multiple dosing, few
drug interactions
• Dose dependent prolongation of prothrombin time
CM Gibson 2007
Rivaroxaban Clinical Development Program
• Ongoing evaluation in acute
and chronic settings for
prevention and treatment
of multiple venous and
arterial indications
Target Enrollment Phase II-III
35,000 - 40,000
CM Gibson 2007
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