This document discusses anticoagulation and balancing efficacy and safety in treating blood clots. It covers various anticoagulant, antiplatelet, and antithrombotic drugs used in clinical practice like warfarin, aspirin, clopidogrel, dabigatran, and rivaroxaban. It also explains the coagulation pathway and how different drugs target different steps in coagulation like factor Xa or thrombin. Graphics show outcomes from clinical trials on drug combinations for preventing heart attacks and deaths in patients undergoing procedures.

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2. Anticoagulation: The Art of Balance
Both efficacy and safety are
important, imbalance in
efficacy and safety may result
in patient harm

3. 1. Safety versus Efficacy
2. Thrombosis = Clotting + Coagulation
3. AntiThrombotics That Have Changed Clinical Practice
a) Anticoagulants
b) Antiplatelets
c) Anticlotting
4. AntiCoagulants
a) Aspirin
b) Warfarin
5. AntiPlatelets
a) Clopidogrel
b) Ticragrelor
c) Bivalrudin
6. AntiClotting
a) Dabigatran
b) Apixiban
c) Rivaroxaban

4. Optimal Safety
Thrombosis and Efficacy
Bleeding
Dose (concentration) of Anticoagulant

5. TF (Tissue Factor)
XI XIa
Intrinsic Pathway
IX IXa VIIa + TF VII
VIIIa Extrinsic Pathway
X Xa
Intrinsic or Extrinsic pathway
activation leads to thrombin Va
formation via the final common II IIa (Thrombin)
coagulation pathway
Fibrinogen Fibrin

6. Anticoagulants
 Low-molecular-weight heparin
Antiplatelet Drugs
 Thienopyridines
 Glycoprotein IIb/IIIa Inhibitors
Anticlotting Drugs
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8. <48 hrs after rand PCI ≥ 48 hrs from rand and PCI after hospital
during initial hosp discharge
0.20 0.20 0.20
Cumulative Hazard Rates Death / MI
Denotes median
Time to PCI ASA
ASA
0.15 0.15 0.15
ASA
0.10 0.10 0.10
ASA + Clopidogrel ASA + Clopidogrel
0.05 0.05 0.05
ASA + Clopidogrel
RR:0.53 (0.27-1.06) RR:0.72 (0.51-1.01) RR:0.70 (0.48-1.02)
0.0 0.0 0.0
0 100 200 300 0 100 200 300 0 100 200 300
Days of Follow-up Days of Follow-up Days of Follow-up
Lewis BS, et al. Am Heart J. 2005;150:1177-1184.

9.  Angioscopic findings
100%
83%
suggestive of plaque
79%
80% instability are extremely
70% 71%
frequent (75% to 80% of
60% the study population) as
is the presence of clot
s ub m r h T y poc o gn A n o
40% even in the absence of
clinical symptoms.
20%
% s i
 Only 16% of clot seen
0% on angio
< 8 Days 8<& 10 < & > 15 Days
(n=18) < 10 Days < 15 Days (n=14)
o
(n=10) (n=14)
Days after lysis or medical therapy Van Belle et al. Circulation. 1998;97:26-
33.

10. Rates of Recurrent MI
Rothberg et al. Ann. Int. Med. 2005;143:241-250

11. 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
30
Major Bleed
Death,MI,CVA
Tranfusion
20
Minor Bleed 15
%
10 8
5
1 1 1 1 2 1
0
ASA Coumadin Combo
Rate of
Discontinuation
10% 19% 20%
van Es et al Lancet 360:109,2002

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13. 1

15.  ⇒ Effective
 Rapid onset and offset of action
 ⇒ Safe
 Predictable PK and PD
 Wide therapeutic window
 ⇒ Easy
 No need for monitoring
 Oral, preferably once daily
 Fixed doses
 Low propensity for food and drug interactions

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17. ORAL PARENTERAL
TF/VIIa TFPI (tifacogin)
TTP889
X IX
Rivaroxaban IXa APC (drotrecogin alfa)
Apixaban VIIIa sTM (ART-123)
LY517717
Va
YM150 AT Fondaparinux
DU-176b Xa
Idraparinux
Betrixaban
TAK 442
II DX-9065a
Dabigatran IIa
Fibrinogen Fibrin
apted from Weitz & Bates, J Thromb Haemost 2007

18. Tissue
XIIa factor
XIa VIIa
IXa
Xa
II
×Factor IIa
(thrombin)
Dabigatran

19.  Dabigatran doses of 150 and 220 mg once daily (od) were
investigated in all three studies
Study Type of Comparator Number of Time to 1st Treatment
surgery patients administration duration
of dabigatran
RE-MODEL TKR Enoxaparin 2010 1–4 hours 6–10 days
40 mg od, starting post-surgery
evening before
surgery
RE-MOBILIZE TKR Enoxaparin 2615 6–12 hours 12–15 days
30 mg bid, starting post-surgery
12–24 hours post-
surgery
RE-NOVATE THR Enoxaparin 3494 1–4 hours 28–35 days
40 mg od, starting post-surgery
evening before
surgery
TKR: total knee replacement; THR: total hip replacement
Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007

20. Enoxaparin Dabigatran Dabigatran
(150 mg) (220 mg)
DVT, PE and all-cause mortality (%)
RE-NOVATE 6.7 8.6 6.0
p<0.0001* p<0.0001*
RE-MOBILIZE 25.3 33.7 31.1
p=0.0009 †
p=0.02†
RE-MODEL 37.7 40.5 36.4
p=0.0005* p=0.0345*
Major bleeding (%)
RE-NOVATE 1.6 1.3 2.0
RE-MOBILIZE 1.4 0.6 0.6
RE-MODEL 1.3 1.3 1.5
*Non-inferior to enoxaparin; †inferior to enoxaparin
Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007

21. Tissue
XIIa factor
×
XIa VIIa
IXa
Rivaroxaban
Xa
Apixaban
YM150
DU-176b
LY517717
Factor II Betrixaban
(prothrombin) TAK 442
Fibrinogen Fibrin clot

22.  Oral, direct, selective factor Xa
O
inhibitor
 Produces concentration-dependent N NH2
anticoagulation N
 No formation of reactive
intermediates
O O N
 No organ toxicity or LFT abnormalities
in chronic toxicology studies
 Low likelihood of drug interactions or
QTc prolongation
 Good oral bioavailability N O
 No food effect
 Balanced elimination (~25% renal)
 Half-life ~12 hrs
He et al., ASH, 2006, Lassen, et al ASH, 2006

23.  Apixaban od and bid (total daily doses 5-20mg) were assessed
relative to enoxaparin and warfarin, in 1,217 patients
Total VTE and All-Cause Mortality (%)
Total VTE and All-Cause Mortality (%) Major Bleeding (%)
Major Bleeding (%)
30 26.6 30
25 25
Percent
Percent
20 20
15.6
15 15
10.6
10 8.6 10
6.8
5 5 3.0
1.3 1.6
0 0
0 0
Enoxaparin Enoxaparin
5mg 10mg20mg Warfarin
(INR (30mg bid) 5mg 10mg20mg Warfarin
(INR (30mg bid)
Apixaban 1.8-3.0) Apixaban 1.8-3.0)
(Total Daily Dose) (Total Daily Dose)
Lassen et al. Blood 2006

24.  Apixaban bid (5 and 10mg) and od (20mg) were assessed
relative to low molecular weight heparin (LMWH) or
fondaparinux followed by VKA, in 520 patients
Composite of Symptomatic
Composite of Symptomatic
Recurrent VTE and Deterioration
Recurrent VTE and Deterioration Major Bleeding (%)
Major Bleeding (%)
of Thrombotic Burden (%)
of Thrombotic Burden (%)
10 10
8 8
6.0
6 5.6 6
Percent
Percent
4.2
4 4
2.6
2 2 0.8
0.8
0 0
0 0
5mg 10mg 20mg LMWH/ 5mg 10mg 20mg LMWH/
fondaparinux fondaparinux
bid bid bid + VKA bid bid bid + VKA
Apixaban Apixaban
Büller, Eur Heart J 2006

25. Agent Disadvantages
Heparin • Parenteral administration
• Risk of heparin-induced thrombocytopenia (HIT)
• Narrow therapeutic window (low bioavailability, short
half-life)
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 • Parenteral administration
Inhibitor • Long half-life
(e.g. fondaparinux) • Limitations related to special patient populations
Direct • Parenteral administration
Thrombin • Current applications limited to cardiovascular
Inhibitors management
Albans S et al. Eur J Clin Invest 2005;35(Suppl 1):12-20.

26.  Predictable O
Cl
pharmacology
O S
O N N H
N
O
O
Rivaroxaban® – rivaroxaban
 High bioavailability
 Low risk of drug–drug
interactions
 Fixed dose
 No requirement for
monitoring
Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005

27.  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

28. XIa TF (Tissue Factor)
XI
Intrinsic Pathway
IX IXa VIIa + TF VII
Extrinsic Pathway
VIIIa
X Xa
If either Intrinsic or Extrinsic
pathway is activated, Rivaroxaban Va
blocks the final common II IIa (Thrombin)
coagulation pathway leading to
thrombin formation by blocking
Factor Xa Fibrinogen Fibrin

29.  Two large, phase II studies of rivaroxaban for 3 mo for
treatment and long-term secondary VTE prevention:
› ODIXa-DVT : Rivaroxaban 10–30 mg bid
and 40 mg od
› EINSTEIN DVT : Rivaroxaban 20–40 mg od
› LMWH followed by VKA comparator in both studies
Agnelli et al. Circulation 2007; Büller. Eur Heart J 2006

30. Oral rivaroxaban compared with
subcutaneous enoxaparin for
extended thromboprophylaxis after
total hip arthroplasty

31. 5
Rivaroxaban 10 mg once daily
Total VTE Enoxaparin 40 mg once daily
4 RRR 70%
Incidence (%)
3
Major VTE
RRR 88%
2
Symptomatic VTE
1 Major
bleeding
3.7% 1.1% 2.0% 0.2% 0.5% 0.1%
0.3% 0.3%
0

32. Extended thromboprophylaxis with
rivaroxaban compared with short-term
thromboprophylaxis with LMWH
after total hip arthroplasty

33. 10
Total VTE Rivaroxaban 10 mg once daily
Enoxaparin 40 mg once daily
8
Incidence (%)
6
Major VTE
4
Symptomatic
RRR 78.9% VTE
2 Major bleeding
RRR 87.8%
RRR 80.1%
9.3% 2.0% 5.1% 0.6% 1.2% 0.2% 0.1% 0.1%
0

34. Rivaroxaban – an oral, direct Factor Xa inhibitor –
for the prevention of venous thromboembolism in
total knee arthroplasty surgery

35. Total VTE
20
RRR 49%
Enoxaparin 40 mg
od
Rivaroxaban 10
15 mg od
Incidence (%)
10
Major VTE
5 Symptomatic VTE
Major bleeding
RRR 62% RRR 65%
NS
18.9% 9.6% 2.6% 1.0% 2.0% 0.7% 0.5% 0.6%
0

36. 70
Rivaroxaban 1.25 mg (n=8)
Rivaroxaban 5 mg (n=6)
60
Rivaroxaban 10 mg (n=8)
50
Anti-Xa Activity Rivaroxaban 20 mg (n=7)
% Inhibition of Factor Xa
Rivaroxaban 40 mg (n=8)
40 Rivaroxaban 80 mg (n=6)
Placebo (n=25)
30
20
10
0
-10
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)
► All once-daily dosage regimens demonstrated
Xa inhibition for out to 24 hours
► These results provided foundation for selection of
Kubitza, et al. Clin Pharmacol Ther 2005;78(4):412-21. once-daily dosing regimen for Phase III programs

37.  Specific, competitive,
direct FXa inhibitor
 Inhibits free and clot-
associated FXa activity, 100
and prothrombinase
Inhibition of Factor Xa activity (%)
activity 80
 Inhibits thrombin
generation via inhibition of
FXa activity 60
◦ Prolongs time to thrombin 40
generation
◦ Inhibits peak thrombin 20
Free FXa
generation Prothrombinase activity
Clot-associated FXa
◦ Reduces the total amount 0
of thrombin generated 0.01 0.1 1 10 100 1000
Rivaroxaban (nM)
 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. In press

38. • Dose peaks in 2.5–4 hrs, t1/2=5-9 hrs (11-13 hrs in elderly)
• One dose will be selected for clinical use
• No monitoring required given consistent dose response
• Dual modes of excretion
•Renal (66%), no excess bleeding associated with CrCl
•Fecal/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

39. Rivaroxaban: Anti-Thrombotic Efficacy
100 *P<0.05 ; **P<0.01
** • Arterial thrombosis
80
Thrombus reduction (%)
rabbit arteriovenous
shunt model
*
60 • Rivaroxaban dose-
dependently prevented
arterial thrombosis
40
20
0
0.3 1.0 3.0
Rivaroxaban (mg/kg) p.o.

40. Primary
 Total venous thromboembolism (VTE): any
deep vein thrombosis (DVT), 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

41. Rivaroxaban Safety: Bleeding Time
Tail Transection Bleeding Time in Rats
X-fold prolongation of
Compound 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

42. 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

43. Rivaroxaban: Bleeding Time with
Combination Therapy
Tail Transection Bleeding Time in Rats
X-fold prolongation
Compounds
of bleeding time
Clopidogrel 1 mg/kg [po]
2.1 +/- 0.3
Aspirin 3 mg/kg [po]
Clopidogrel 1 mg/kg [po]
Aspirin 3 mg/kg [po]
2.5 +/- 1
+
Rivaroxaban 0.1 mg/kg [iv]
Similiar Bleeding Times

44. DVT, PE, and all-cause mortality Major, post-operative bleeding
30
Incidence rate %
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

45.  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 59-7939 did not exceed the level observed
with enoxaparin
› There was no dose-dependent increase in transaminase levels
Liver function
test (LFT) Rivaroxaban Enox
5 mg 10 mg 20 mg 30 mg 40 mg 40 mg
ALT > 3× ULN 5/119 6/133 4/133 7*/129 5/127 10/140
% 4.2 4.5 3.0 5.4 3.9 7.1
*One patient had ALT >3× ULN and bilirubin >2× ULN (occurring before first intake of study
drug)

46. Phase II Phase III
VTE prevention after major  ODIXa-HIP1
orthopaedic surgery  ODIXa-HIP2
 ODIXa-KNEE  RECORD1
 ODIXa-OD-HIP  RECORD2
 RECORD3
 RECORD4
VTE prevention in
hospitalized medically ill
patients
VTE treatment  ODIXa-DVT
 EINSTEIN-DVT  EINSTEIN-DVT
 EINSTEIN-PE
 EINSTEIN-EXT
Stroke prevention in atrial
fibrillation Japanese Phase III study
Secondary prevention of
acute coronary syndromes
~8,000 >42,000

47. Rivaroxaban
CM Gibson 2007

48. Safety
Rivaroxaban
Efficacy Ease
CM Gibson 2007

49.  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

50.  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

51. • Ongoing evaluation in acute
and chronic settings for Target Enrollment Phase II-III
prevention and treatment
of multiple venous and
35,000 - 40,000
arterial indications
CM Gibson 2007

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