1. Prof. Rosanna Abbate Univ.di Firenze

2. Commonly-used anticoagulant treatments affect several steps of coagulation pathway
Intrinsic pathway
Extrinsic pathway
XII
XIIa TF
VII XI
XIa
VIIa
VIIIa
Ca2+ PL
IXa PS IX
Ca2+
Legend PC
PCa TM
Coagulation mechanisms Xa X Xa
Endogenous anticoagulant
ATIII Xa Va PL
Ca2+
TFPI
ATIII
Inhibition by heparins
IIa II
Inhibition by Vitamin K
antagonists
Fibrinogen
Fibrin
Clot

3. Anticoagulant drugs currently used
Heparins (standard unfractionated, low molecular weight)
Oral anticoagulants (warfarin, acenocumarol)
Hirudin (in Italy only for HIT)

4. New agents in clinical development: The search for selectivity
Thrombin Inhibitors: DS, Hirudin, Bivalirudin, Argatroban, Melagatran, Ximelagatran
IXa inhibitors
Xa inhibitors:
Pentasaccharide
TAP, Antistasin, DX 9065a, DPC 906
Protein C Activators
aPC, Thrombomodulin
Coagulation Pathway
Antithrombotics in development
Tissue Factor Pathway Inhibitors
TFPI, rNAPc2, VIIa inhibitors
Initiation
Thrombin
generation
activity
TF/VIIa X IX
IXa
VIIIa Xa Va II
IIa i

5. Vascular tone regulation Vascular release of TPA
Thrombin functions
Platelet activation
F V and F VIII activation
Vascular tone regulation
Fibrin formation
Cellular migration
F XIII activation
Mitogenic activity
Protein C activation
Vascular release of TPA
TAFI

6. TROMBINA: siti funzionali
Anion binding exosite II
heparin binding site
Catalytic site
THROMBIN
FIBRINOGEN
Anion binding exosite I
fibrinogen binding site

7. COMPARISON OF INHIBITORY EFFECTS OF HEPARIN ON
FLUID-PHASE ( ) AND FIBRIN-BOUND THROMBIN ( )

10. Farmaci antitrombinici
AT III
HEPARIN
MELAGATRAN BSF
BIBR 1048 MS
THROMBIN
HIRUGEN
LU 58463
HIRUDIN
HIRULOG

11. Ximelagatran
The drug has a half-life of about 3 h mandating twice daily administration. The active agent, melagatran, is primarily eliminated via the kidneys. Consequently, its half-life is prolonged in the elderly, reflecting their reduced renal function. The pharmacokinetics and pharmacodynamics of ximelagatran are not influenced by aspirin and ximelagatran does not interfere with drugs that are metabolized by the P450 isozymes CYP2C19, CYP2C9 or CYP3A4
Weitz, et al. Thrombosis Research 106; 2002

12. XIMELAGATRAN (H 376/95) pro-drug oral administration melagatran
tmax melagatran h
half life of melagatran
h (healthy vol.)
bioavailability of melagatran of approx 20%
low variability in melagatran exposure
dose, time, gender independent
no food interaction (minor decrease in AUC <10%)

13. MELAGATRAN subcutaneous dosing bid
rapidly and complete absorption subcutaneously
low volume of distribution 0.2 L/kg
plasma protein binding <15%
not metabolised
clearance mainly (80%) renal
tmax 0.5 h
half life h (healthy subjects)
inter-individual variability of AUC low (CV; about 15%)
NOT suitable for oral dosing

14. Melagatran LMW selective direct thrombin inhibitor
Synthetic compound - molecular weight of approx 400
EXOSITE 1
(also binding site of fibrin)
THROMBIN
ACTIVE SITE

15. Melagatran Synthetic compound - mol w of approx 400 -Directed to the Active Site of Thrombin
Hirudin
also binding
site of fibrin
Hirulog
Exosite 1
Exosite 1
Exosite 1
Melagatran
Thrombin (with indirect
blocked active site)
H376/95 is an oral prodrug of Melagatran directed to the active
site of thrombin
• Exosite 1 is the main fibrin binding site of thrombin and is occupied in clot-bound thrombin. The active site, which is responsible for physiological thrombin activity, is free in both circulating and clot-bound thrombin.
• Long chain thrombin inhibitors occupy exosite 1 when they bind to thrombin. They therefore have limited activity against clot-bound thrombin.
• Melagatran binds to the active site of thrombin but not exosite 1. Both clot-bound and circulating free thrombin are inhibited by Melagatran.
Thrombin (with
binding to active site)
Thrombin (with
binding to active site)
Adapted from Lefkovits. Circulation 1994;90:1522–1536.

16. Melagatran

19. Melagatran e’ il metabolita attivo di Ximelagatran
Biodisponibilita’ 20% (dose orale 60 mg, n=12)
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Ximelagatran
- t max 1.5 h
- emivita 3 h
- eliminazione
renale
Melagatran
Plasma conc. (µmol/l) 2 4 6 8 10 12
Time (h)
Eriksson, Blood, 1999

20. Antithrombotic effect and bleeding in a rat model
Thrombus size (AU)
Total bleeding time (min) 20 50
Warfarin 40 15
Melagatran 30 10 20 5
Effect 10
Bleeding
0.01
0.1 1 10
Dose (µmol/kg/h) , (µmol/kg/day)
Elg M et al, Thromb Res 1999;94:187

21. Melagatran/ximelagatran Studi clinici sperimentali
Fase I
TEV
profilassi FA
terapia
SCA
Melagatran
- 22 studi
H 376/95
- 24 studi
TR2-0002
TR2-0005
METHRO I
METHRO II
MASCOT I
203 (USA)
METHRO III
PLATINUM
EXPRESS
EXULT A
EXULT B
TR2-0001
THRIVE I
THRIVE IV
THRIVE III
THRIVE II
THRIVE V
SPORTIF II
SPORTIF III
SPORTIF IV
SPORTIF V
ESTEEM

22. EXPRESS: disegno dello studio
M e l a g a t r a n sc
Ximelagatran orale 24 mg bid (mattino e sera)
2 mg
3 mg
2835
THR/
TKR pts
Enoxaparina mg sc qd (ogni sera)
sera op sera
Tempo h h h h gg sett
flebografia follow-up
Each administered with matched placebo
Treatment: 7-12 days F-up: 4-6 wks
Eriksson, JTH 2003

23. EXPRESS: TVP Prossimale + PE
RRR = 60%
% event 9
RRR=63.2%
RRR=67% 8 7 6
melagatran (sc) and ximelagatran (po) 5 4
enoxaparina(sc) 3 2 1
THR interventi
TKR Interventi
THR+TKR Interventi
Eriksson, JTH 2003

24. EXPRESS: TEV totali VTE sintomatico raro RRR=21% RRR=23.6% RRR=29%
% eventi 50 40
RRR=23.6%
RRR=29%
melagatran (sc) and ximelagatran (po) 30 20
enoxaparina(sc) 10
THR Interventi
TKR Interventi
THR+TKR Interventi
Eriksson, JTH 2003
VTE sintomatico raro

25. EXPRESS: Emorragie Maggiori
Surgery Bleeding Category Enoxaparin Melagatran/ Ximel.
THR+ ITT population
TKR -Fatal Bleeding
-Critical Site
-Severe % 3.1%
-Other % 9.2%
-Non wound related
transfusion > 2 units %
-Requiring re-operation# 0.4% %
-Blood transfusions 61.7% 66.8%*
May have occurred during the entire study period
* Difference significant for THR, not for TKR
Eriksson, JTH 2003

26. Proximal DVT/PE, % (95% Cl) Blood loss during surgery, mL (95% Cl)
Efficacy and safety of (xi)melagatran for prevention of VTE after THR or TKR:
analysis of 3 randomized, double-blind studies, to evaluate the influence of time and dose
Treatment/
Preoperative dose
Proximal DVT/PE, % (95% Cl)
Total DVT/PE, % (95% Cl)
Bleeding, % (95% Cl)
Blood loss during surgery, mL (95% Cl)
Melagatran/0 mg (METHRO III)
5.7 (4.4;7.2)
31.0 (28.3;33.7)
1.4 (0.9;2.2)
211.8 (190.3;235.7)
Melagatran/2 mg (EXPRESS)
2.3 (1.5;3.3)
20.2 (17.9;22.7)
3.3 (2.4;4.4)
195.4 (175.5;217.6)
Melagatran/3 mg (METHRO II)
2.4 (1.0;4.9)
15.1 (11.1;19.8)
4.8 (2.8;7.4)
215.0 (175.0;264.2)
LMWH (pooled data)
6.3 (5.4;7.3)
27.1 (25.4;28.8)
1.5 (1.1;2.0)
205.7 (191.6;220.9)
A. T. Cohen, ISTH 2003

27. EXULT A TRIAL TKR Ximelagatran (24 mg bid) Ximelagatran (36 mg bid)
(++North-America)
Ximelagatran (24 mg bid)
Ximelagatran (36 mg bid)
Warfarin (INR 1.8-3)
TKR
Each administered with matched placebo
Treatment: 7-12 days F-up: 4-6 wks
Warfarin initiated the evening of the day of surgery
Ximelagatran initiated 12 hrs or more after surgery
Francis NEJM 2003

28. EXULT A - Efficacy end points
Warfarin (95% CI)
Ximelagatran 24 mg (95% CI)
Ximelagatran 36 mg (95% CI)
Total VTE and death
27.6%
( )
24.9%
( )
20.3%
( )*
Proximal VTE and death
4.1%
( )
2.5%
( )
2.7%
( )
*p=0.003 RRR 26.4% ARR 7.3%
Symptomatic DVT or death < 1% in each group
Francis NEJM 2003

29. EXULT A: Safety end points
Warfarin (95% CI)
Ximelagatran 24 mg (95% CI)
Ximelagatran 36 mg (95% CI)
Major bleeding
0.7% ( )
0.8% ( )
Major or minor bleeding
Minor bleeding
4.5% ( )
4.0%
4.8% ( )
4.7%
5.3% ( )
No statistically significant differences for perioperative indicators of bleeding, or wound drainage or appearance
Francis NEJM 2003

31. EXULT B TRIAL TKR Ximelagatran (36 mg bid) Warfarin (INR 1.8-3)
(++North-America)
Ximelagatran (36 mg bid)
Warfarin (INR 1.8-3)
TKR
Study design very close to EXULT A
2303 pts enrolled, 2299 received at least one dose, 1949 had adequate venography
Weitz ISTH 2003

32. EXULT B: Total VTE and all-cause mortality
End point
Warfarin (%)
Ximelagatran (%)
RRR (%) p
Total VTE and all-cause mortality event rate
31.9
22.5
29.3
<0.001
ARR 9.3% (95% CI ) NNT 11 (8-18)
A trend was observed to reduction of proximal DVT (4% vs 3.5%)
Colwell CW et al. American Society of Hematology; December 6-9, 2003; San Diego, CA.

33. EXULT B: Bleeding events
End point
Warfarin (%)
Ximelagatran (%) p
Major bleeding
0.4
1.0 NS
Minor bleeding
3.4
4.2
No relevant alterations in liver function tests as in EXULT A
Colwell CW et al. American Society of Hematology; December 6-9, 2003; San Diego, CA.

34. (Xi)melagatran in chirurgia ortopedica maggiore
USA
Xi 24 mg x2 = enoxa 30 x2 in TKR
Xi 24 mg x2 = W in TKR
Xi 24 mg x2 < enoxa 30 x2 in THR
Xi 36 mg x2 > W in TKR (EXULT)
M 3 mg pre e 3mg post + Xi 24 mg x2 > dalte 5000 x1 ma > emorragie in THR+TKR
M 2 mg pre e 3mg post + Xi 24 mg x2 > enoxa 40 x1 in THR+TKR (EXPRESS)
M 3mg post + Xi 24 mg x2 = enoxa 40 x1 in THR+TKR
Europa
D Prisco 2004

35. Timing of initial administration of prophylaxis against deep vein thrombosis in patients following hip or knee surgery (Hull 2003)
Quadratic fit for study OR for DVT vs. the number of hrs from surgery for the first dose of the antithrombotic regimen. Peak efficacy ranges between 2 h preop and 6-8 h postop.

36. DVT treatment, THRIVE I - Study design
Ximelagatran 24 mg oral bid
n=68
N=350 DVT pts
Ximelagatran 36 mg oral bid
Multicentre, randomised,
controlled, parallel group,
dose-finding
n=65 R
Ximelagatran 48 mg oral bid
n=73
Ximelagatran 60 mg oral bid
n=71
Dalteparin sc + warfarin
n=73
Visit 1
Visit 2
Visit 3
Visit 14
Visit 5
Pre-entry
Day 3-5
Day 6-9
Day 12-16
Day 26-32
Phlebography
Phlebography
Follow-up
Adv Ev
Eriksson H et al. J Thromb Haemost 2003; 1: 41-7.

37. THRIVE I - treatment of patients with DVT Ximelagatran (24 - 60 mg bid) vs warfarin + dalteparin
Efficacy: Change in Marder score units at 14 days (n=295)
24 mg
36 mg
48 mg
60 mg
W/D 10 20 30 40 50 60 70
<-5
[-5 to +5]
>5
Patients %
Total bleeding: Ximelagatran (12 %, no dose response), W/D (10 %)
Eriksson H et al. J Thromb Haemost 2003; 1: 41-7.

38. THRIVE I- Conclusions:
H 376/95 in DVT
Flat dose-response
Broad therapeutic interval
No severe bleedings
Use without monitoring supported

39. THRIVE II: design of the study
Warfarin or H 376/95
n= 1241
H 376/95 36 mg b.i.d. + Placebo Warfarin/Enoxaparin
stratification R
37% enrolled pts with PE
Placebo H 376/95 + Warfarin/Enoxaparin E
Enoxaparin
(1 mg/Kg bid)
End of Treatment
24 hours
n= 1250
max 14 days
Until INR  2.0 at two consecutive measurements
( days of Enoxaparin)
6 Month
14 days follow up
Objective confirmation of DVT and/or PE
onset of symptoms of DVT of lower limbs
+/- PE

40. THRIVE II: results Event Ximelagatran n (%*) Enoxa/warfarin n (%*)
Absolute difference ximel: enoxa/w (%*; 95% Cl)
Recurrent VTE (ITT)
26 (2.1%)
24 (2.0%)
+0.2%** (-1.0%; + 1.3%)
Recurrent VTE (OT)
23 (2.0%)
17 (1.5%)
+0.5% (-0.6%; + 1.6%)
All-cause mortality (ITT)
28 (2.3%)
42 (3.4%)
-1.0%** (-2.4%; + 0.2%)
Major bleeding (OT)
14 (1.3%)
25 (2.2%)
-0.9% (-2.0%; + 0.2%)
Recurrent VTE and/or major bleeding (OT)
37 (3.2%)
42 (3.6%)
-0.4% (-1.9%; + 1.1%)
*Estimated cumulative risk; **rounded figures; CI = confidence interval; ITT = intention-to-treat; OT = on-treatment

41. Volume 349:
    
October 30, 2003
Number 18
Secondary Prevention of Venous Thromboembolism with the Oral Direct Thrombin Inhibitor Ximelagatran
Sam Schulman, M.D., Karin Wåhlander, M.D., Torbjörn Lundström, M.D., Solveig Billing Clason, M.Sc., Henry Eriksson, M.D., for the THRIVE III Investigators

42. THRIVE III: disegno dello studio
ITT
population
Initial VTE
event
Ximelagatran (24 mg, b.i.d., p.o.)
Stratification - malignancy
617 patients
n=612 E R
616 patients
n=611
Placebo
Stop of study treatment
INR<1.5
Standard anticoagulation
Study treatment
6 ±1 months
18 months
2 weeks follow up
Leg US scan + perfusion
lung scan at baseline
Schulman, NEJM 2003

43. THRIVE III: TEV totali - TVP e/o EP (ITT population)
Estimated
cumulative risk (%) 2 4 6 8 10 12 14
12.6%
P<0.0001
HR=0.16 (95%CI 0.09; 0.30)
9.8% 3 6 9 12 15 18
Months
Ximelagatran
Placebo
2.8%
Schulman, NEJM 2003

44. THRIVE III: Emorragie maggiori e minori (ITT population)
Estimated
cumulative risk (%) 30 25
P= (NS)
HR=1.19 (95%CI 0.93; 1.53)
21.0%
23.9% 20 15
Ximelagatran 10
Placebo 5 3 6 9 12 15 18
Months
Schulman, NEJM 2003

45. Ridker PM et al, N Engl J Med 2003

46. THRIVE III Placebo Ximelagatran Emorragie maggiori * 0.8% 1.0% Morti
Morti +TEV
1.2%
13.3%
3.9% HR 0.23
Aumento ALT
(>3 x limite superiore normale)
6.4%**HR 6.5
*nessuna fatale o intracranica
** Senza iperbilirubinemia, massimo valore osservato 25 x, mesi, transitorio, andamento indipendente da sospensione ximelagatran o meno, non segni o sintomi, non spiegabile con caratteristiche di pazienti o farmaci associati
Schulman, NEJM 2003

47. Time Courses of Elevations in the Alanine Aminotransferase Level in Patients Receiving Ximelagatran in Whom the Values Exceeded Three Times the Upper Limit of Normal at Least Once
Diamonds represent the last observation in a given patient; dotted lines represent patients in whom treatment with ximelagatran was discontinued. The highest peak shows the maximal elevation in a patient with positive serologic-test results for Epstein–Barr virus infection. The outlying peak near 360 days shows the maximal elevation in a patient with a gall-bladder concrement.
Schulman, NEJM 2003

48. ® Fibrillazione atriale – Fase III Ximelagatran 36 mg bid Warfarin
Fino a 27 mesi
3000 paz. “resto del mondo” open label, : SPORTIF III
3000 paz. USA & Canada double-blind,
double-dummy, sham INR : SPORTIF V

49. Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF III)
Lancet 2003;362:

50. The SPORTIF III Study Warfarin ximelagatran Adjusted-dose (INR 2-3)
Fixed-dose
ximelagatran
(36 mg b.i.d.)
Nonvalvular atrial fibrillation patients with
at least one aditional risk factor for stroke
n=3 407
Randomised, parallel group, open-label treatment allocation, blinded event assessment
23 countries, 259 centers
Exposure: mean 17 months, 4941 patient-years and 96 primary endpoints.
Primary objective:
To establish the non-inferiority of ximelagatran compared to dose-adjusted warfarin (INR ) for prevention of all strokes and/or systemic embolic events in patients with nonvalvular paroxysmal or persistent atrial fibrillation and 1 adjunctive risk factor for stroke

51. Paragone di vari eventi compositi
SPORTIF III, Lancet 2003;362:

52. SPORTIF III Stroke e/o embolia sistemica (intention to treat)
56 eventi (2.3%/anno) 1 2 3 4
p=0.10
40 eventi (1.6%/anno)
Eventi cumulativi (%)
Warfarin
Ximelagatran 3 6 9 12 15 18 21
Durata (mesi)
Presented at ACC 2003

53. Eventi avversi maggiori (on treatment analysis)
Eventi (% per anno)
Warfarin 14
RRR=25% p = 0.022
Ximelagatran 12 10 8
6.1% 6
4.6% 4 2
Eventi primari + emorragie maggiori + morte
Presented at ACC 2003

54. Altri eventi avversi Aumento enzimi epatici
Warfarin 14
Ximelagatran 12 10
p <0.001 8
6.5% 6 4 2
0.7%
ALT >3x limite sup. norma
Presented at ACC 2003

55. The SPORTIF V Study Warfarin Ximelagatran Adjusted-dose (INR 2-3)
Fixed-dose
Ximelagatran
(36 mg bid)
Nonvalvular atrial fibrillation patients with
at least one aditional risk factor for stroke
n=3 922
Randomised, double-blind, double-dummy, sham INR, blinded endpoint assessment
USA and Canada, 409 centers
Exposure: mean 20 months, 6405 patient-years and 88 primary endpoints.
SPORTIF V, the largest stroke prevention study in atrial fibrillation to date, including 3922 patients with moderate to high risk for stroke is a further landmark study comparing the first oral in a new class of direct thrombin inhibitor ximelagatran with dose-adjusted warfarin. The key results of SPORTIF III, which involved open-label treatment according to the same protocol, were reported earlier this year.
The protocol stipulated a minimum exposure of 12 months per patient, an aggregate follow-up of more than 4,000 patient-years, and at least 80 patients with verified primary events.
The primary analysis was based on intention-to-treat and compared the combined rates of all strokes (ischemic or hemorrhagic) and systemic embolic events in patients assigned to ximelagatran with those assigned to warfarin. Although the SPORTIF program included two independently powered trials, the analysis plan also called for pooling the event rates from both to examine the relative effects of warfarin and ximelagatran on events occurring at low frequencies.
The efficacy of warfarin in patients with atrial fibrillation made a placebo control unethical. Hence the study was designed to evaluate whether ximelagatran was at least as effective as warfarin within a pre-specified margin of 2% for the difference in primary event rates.
Primary objective:
To establish the non-inferiority of fixed-dose ximelagatran compared to dose-adjusted warfarin (INR ) for prevention of all strokes and/or systemic embolic events in patients with nonvalvular paroxysmal or persistent atrial fibrillation and 1 adjunctive risk factor for stroke

56. SPORTIF V - Stroke ed embolismo sistemico (Intention to treat)
Eventi cumulativi (%/anno) 1 2 3 4 5 7 6
Warfarin
Ximelagatran
51 events (1.6%/anno)
p=0.13
37 eventis (1.2%/anno)
The SPORTIF V study met its primary objective of non-inferiority for ximelagatran in prevention of stroke and other thromboembolic complications when compared to well-controlled, dose-adjusted warfarin. 3 6 9 12 15 18 21 24
Mesi
Ximelagatran Warfarin

57. SPORTIF (Analisi intention to treat)
Ximelagatran meglio
Warfarin meglio
-0.66
SPORTIF III
+0.45
SPORTIF V
-0.03
Pooled
When the entire SPORTIF phase III program is considered, ximelagatran is consistently associated with a low rate of thromboembolism, 1.6% per year. In patients assigned to warfarin, the event rate in the SPORTIF V trial is about half that in SPORTIF III, despite similar clinical risk profiles and anticoagulation intensity. The reason for this apparent disparity in warfarin efficacy is not clear, but patient, laboratory or other clinical factors may be responsible, or simply the play of chance.
Taken individually, each of the large-scale SPORTIF trials satisfies the criteria in the primary analyses to establish the noninferiority of ximelagatran compared to warfarin.
-1.5 -1
-0.5
0.5 1
1.5 2
Differenza assoluta nella frequenza di eventi (Ximelagatran – Warfarin)

58. SPORTIF V - Emorragie (Analisi on treatment)
Eventi (% /anno)
Warfarin 50
47%
Ximelagatran 40
37% 30 20
In the SPORTIF V study, rates of intracranial haemorrhage (ICH) are low with either treatment. Neither is there a significant difference between the groups in rates of major bleeding. A major haemorrhage was either fatal, affected a critical anatomical site, required transfusion, or decreased haemoglobin by 2 grams per decilitre. When minor as well as major events are counted, however, patients randomised to ximelagatran have significantly less bleeding then those given warfarin.
p=0.16 NS 10
3.1%
2.4%
0.1%
0.1%
Cerebrali
Maggiori
Maggiori + minori

59. SPORTIF V - aumento transaminasi ALT >3 x val. normale50
Warfarin
Ximelagatran 40 38 35 30
Numero di pazienti 20
An elevation of ALAT>3XULN was observed in 6% of patients treated with ximelagatran, a consistent level to that seen in other long-term ximelagatran studies. As before, these elevations were typically transient (occurring within fist 2-6 months), decreased towards baseline with treatment continuation or discontinuation and not typically associated with specific clinical symptoms. 10 10 7 6 4 4 3 3 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Mesi

60. Wallentin L et al, Lancet 2003; 362:789-97
Oral ximelagatran for secondary prophylaxis after myocardial infarction. The ESTEEM randomised controlled trial
Wallentin L et al,
Lancet 2003; 362:789-97

61. ESTEEM Study Wallentin L et al. Lancet 2003; 362: 789–97
Dose-finding, doppio cieco, controllato con placebo in 1883 pazienti con recente infarto del miocardio
Ximelagatran 24 mg, 36 mg, 48 mg, or 60 mg 2 volte/die, per 6 mesi
Tutti i pazienti ricevevano anche ASA 160 mg
Obiettivi primari: mortalità generale, infarto non fatale, recidiva ischemica grave

62. ESTEEM Study Wallentin L et al. Lancet 2003; 362: 789–97
Rischio cumulativo di morte, infarto e stroke.
Pool di tutte le dosi di ximelagatran, analisi “intention-to-treat”

63. ESTEEM- Emorragie Wallentin L et al. Lancet 2003; 362: 789–97

64. ESTEEM - Conclusioni Wallentin L et al, Lancet 2003; 362:789-97
L’associazione ximelagatran-ASA è più efficace del solo ASA nella prevenzione di eventi cardiovascolari maggiori nei 6 mesi successivi ad infarto del miocardio

65. What will the future bring us?
Studies so far demonstrate that (xi)melagatran has predictable pharmacokinetic characteristics in volunteers and in patients and has a wider therapeutic window than warfarin.
(Xi)melagatran treatment does not need any lab monitoring
However, no antidote is available for overdosage and the relevance of increase in ALT has to be clarified