Nuovi farmaci antitrombotici: che cosa cambier

1
Nuovi farmaci antitrombotici che cosa cambierà
in clinica nei prossimi anni?

• GF Gensini

Livorno 27 marzo 2004
2
Currently available anticoagulants largely unmet
medical need

• LMWH/heparin
• No oral administration less suited for
  outpatient use
• Risk of heparin-induced thrombocytopenia
• Vitamin K antagonists
• Narrow therapeutic interval, thus frequent
  monitoring required
• Significant food and drug interactions
• Slow on- and offset
• Increased incidence of severe bleeding
  complications
• Limited efficacy as thromboprophylaxis in
  high-risk patients

3
New anticoagulantsUnmet clinical needs

• More effective and safer agents for VTE
  prophylaxis in high risk surgery (major
  orthopedic and cancer)
• More practical agents for post-discharge
  prophylaxis of VTE
• More practical agents for long-term treatment (no
  monitoring) of VTE
• More practical agents for long-term treatment (no
  monitoring) of atrial fibrillation
• Safer adjunctive treatment for STEMI and ACS
• More effective agents for secondary prophylaxis
  of MI

4
New antithrombotic agents
Factor X
FIXa-FVIIIa, Phospholipids, Ca
Tissue factor - FVIIa
Factor Xa
rNAPc2
Pentasaccharide
Prothrombinase complex
Direct anti-Xa inhibitors
Prothrombin
Fibrinogen
Thrombin
Selective anti-IIa inhibitors
5
New anticoagulantsUnmet clinical needs

• More effective and safer agents for VTE
  prophylaxis in high risk surgery (major
  orthopedic and cancer)
• More practical agents for post-discharge
  prophylaxis of VTE
• More practical agents for long-term treatment (no
  monitoring) of VTE
• More practical agents for long-term treatment (no
  monitoring) of atrial fibrillation
• Safer adjunctive treatment for STEMI and ACS
• More effective agents for secondary prophylaxis
  of MI

6
Adjusted-Dose Warfarin Compared with Placebo
Relative Risk Reduction of Stroke (95 CI)
AFASAK I
All cause mortality decreased RRR 26 (4-43)
SPAF
BAATAF
CAFA
SPINAF
EAFT
All trials (n6)
RRR 62 (95 CI 48-72)
100
50
0
- 50
- 100
Warfarin Better
Warfarin Worse
Hart et al Ann Intern Med 1999 131 492-501
7
Optimal Intensity for Warfarin Therapy
15
INR Odds Ratio 2.0 1.0 1.7 2.0 1.5 3.3 1.3 6.
0
10
Odds Ratio for Stroke
5
3
1
1.0
1.5
3.0
4.0
7.0
2.0
INR
N Engl J Med 1996335540-546
8
Aspirin Compared with Placebo
Relative Risk Reduction of Stroke (95 CI)
All cause mortality not significantly decreased
AFASAK I
SPAF I
EAFT
ESPS II
LASAF
UK-TIA
RRR 22 (95 CI 2-38)
All trials (n6)
100
50
- 50
- 100
0
Aspirin Better
Aspirin Worse
Hart et al Ann Intern Med 1999 131 492-501
9
ATRIAL FIBRILLATION INVESTIGATORS
Arch Intern Med 1994
10
Studio ISCOAT età come fattore di rischio per
emorragia
Età anni/paz.
lt 50 y 6.9
50-69 y 5.6
? 70 y 10.5
Analisi univariate ? 70 y vs lt 70 y RR 1.75
(plt0.001) (da Palareti et al. Lancet 1996)
11
(No Transcript)
12
Complications During Long-Term OAC in 360
Patients With AF
Thromboembolic and bleeding events
14.6
4.3
24.4
Bleeding
 Total
13.1
3.4
22.2  
9.6
 Minor
5.8
1.7
 Serious
6.7
1.4
11.8  
 Life-threatening
0.4
0.3
0.4
 Fatal
0.2
0.0
0.4
Thromboembolism
 Total
1.6
0.9
2.1
 Minor
0.1
0.3
0.0
 Serious
1.0
0.7
1.3
 Life-threatening
0.5
0.3
0.0
Values are percentage per 100 patient-years.
P0.0041 P0.0073 P0.0356.
Wehinger C, et al. Stroke 2001 32 2246


13
warfarin
Inizio della TAO
5 mg o meno
dose
1
1
2
2
In pazienti con scompenso cardiaco
Negli anziani
3
4
In pazienti con epatopatia
Bambini 0.2 mg/kg (W)
Br J Haematol 1998
101374 Blood
1999 94 3007
14
Assunzione irregolare di
broccoli e cavoli
Vitamina K gt40 µg/100 g
INR
riduzione
Thromb Haemost 1997 77 504 Haemostasis 1993 23
77
15
Assunzione irregolare di
lattuga
Vitamina K gt40 µg/100 g INR
riduzione
Thromb Haemost 1997 77 504 Haemostasis 1993 23
77
16
Assunzione irregolare di spinaci
Vitamina K gt40 µg/100 g INR
riduzione
Thromb Haemost 1997 77 504 Haemostasis 1993 23
77
17
Assunzione irregolare di fagiolini e carote
Vitamina K 5-40 µg/100 g
18
NECESSITA DI UNA VALUTAZIONE INDIVIDUALE DEL
RAPPORTO RISCHIO BENEFICIO DELLA SCELTA
PROFILATTICA
Il cardiologo dovrebbe appoggiare il paziente ad
un Centro di monitoraggio della TAO ?
19
Un buon monitoraggio della TAO consente di avere
una efficacia ed una sicurezza paragonabili o
migliori di quelle dei trial clinici
20
Un buon monitoraggio della TAO consente di avere
una efficacia ed una sicurezza paragonabili o
migliori di quelle dei trial clinici
21
Cortelazzo et al. 1993
22
Pazienti in trattamento con anticoagulanti orali
in Italia
Stima, Clin Cardiol PD 2002
23
Centri FCSA 2003 N306
24
Considerazioni al momento di decidere il
trattamento con AO (in particolare in un
soggetto di etàgt75 anni)

• Fattori di rischio tromboembolico
• Storia di sanguinamento
• Patologie associate (ad es. ipertensione)
• Grado di attenzione (abbreviated mental test)
• Storia di cadute
• Possibilità di adeguato monitoraggio (più
  accurato e più frequente)
• Supporto familiare e/o sociosanitario

25
New anticoagulantsUnmet clinical needs

• More effective and safer agents for VTE
  prophylaxis in high risk surgery (major
  orthopedic and cancer)
• More practical agents for post-discharge
  prophylaxis of VTE
• More practical agents for long-term treatment (no
  monitoring) of VTE
• More practical agents for long-term treatment (no
  monitoring) of atrial fibrillation
• Safer adjunctive treatment for STEMI and ACS
• More effective agents for secondary prophylaxis
  of MI

26
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
27
Stroke Prevention using an ORal Thrombin
Inhibitor in atrial Fibrillation (SPORTIF III)

• Lancet 20033621691-98

28
The SPORTIF III Study

• 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 2.0-3.0) 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
29
Non-Inferiority Testing
Ximelagatran Superior
Warfarin Superior
Superiority
Non-inferiority
Equivalence
-2
0
2
Absolute Difference in Event Rates
Circulation 20031082723
30
Paragone di vari eventi compositi
SPORTIF III, Lancet 20033621691-98
31
SPORTIF IIIStroke e/o embolia sistemica
(intention to treat)
56 eventi (2.3/anno)
p0.10
40 eventi (1.6/anno)
Eventi cumulativi ()
Warfarin
Ximelagatran
0
3
6
9
12
15
18
21
Durata (mesi)
Presented at ACC 2003
32
Eventi avversi maggiori(on treatment analysis)
Eventi ( per anno)
Warfarin
RRR25p 0.022
14
Ximelagatran
12
10
8
6.1
4.6
6
4
2
0
Eventi primari emorragie maggiori morte
Presented at ACC 2003
33
Altri eventi avversiAumento enzimi epatici
Eventi ()
Warfarin
14
Ximelagatran
12
10
p lt0.001
6.5
8
6
4
0.7
2
0
ALT gt3x limite sup. norma
Presented at ACC 2003
34
The SPORTIF V Study

• 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.

Primary objective To establish the
non-inferiority of fixed-dose ximelagatran
compared to dose-adjusted warfarin (INR 2.0-3.0)
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
35
SPORTIF V - Stroke ed embolismo sistemico
(Intention to treat)
Eventi cumulativi (/anno)
Warfarin
Ximelagatran
51 events (1.6/anno)
p0.13
37 eventis (1.2/anno)
0
3
6
9
12
15
18
21
24
Mesi
Ximelagatran 1960 1900
1596 848 243Warfarin 1962
1910 1624 867 240
36
SPORTIF V - Emorragie (Analisi on treatment)
plt0.0001
Eventi ( /anno)
Warfarin
47
50
Ximelagatran
37
40
30
20
p0.16
NS
10
3.1
2.4
0.1
0.1
0
Cerebrali
Maggiori minori
Maggiori
37
SPORTIF ProgramStroke and Systemic
EmbolismIntention-to-treat Analysis
Cumulative Event Rate (year)
SPORTIF
7
V
III
6
5
4
3
2
1
0
0
3
6
9
12
15
18
21
24
Months
Halperin JL, Presented at AHA 2003
38
SPORTIF (Analisi intention to treat)
Ximelagatran meglio
Warfarin meglio
-0.66
SPORTIF III
0.45
SPORTIF V
-0.03
Pooled
Differenza assoluta nella frequenza di
eventi(Ximelagatran Warfarin)
39
SPORTIF IIIINR Values Warfarin Group
100
gt3.2
80
60
66
81
Time in range ()
2.0-3.0
40
20
lt1.8
0
3
6
9
12
15
18
21
Treatment duration (months)
Lancet 2003
40
SPORTIF VINR Values Warfarin Group
gt3.2
83
68
Time in Range ()
2.0-3.0
lt1.8

Halperin JL, Presented at AHA 2003
41
SPORTIF ProgramMajor BleedingOn-treatment
Analysis
Event Rate ( /year)
4
Warfarin
p0.054
3.1
Ximelagatran
3
2.5
2.4
1.9
2
1.8
1.3
1
0
SPORTIF V
Pooled
SPORTIF III
Halperin JL, Presented at AHA 2003
42
SPORTIF Program ALAT gt3X ULN
Incidence ()
Warfarin
10
Ximelagatran
8
6.3
6.1
6.0
6
4
2
0.8
0.8
0.8
0
SPORTIF V
Pooled
SPORTIF III
Halperin JL, Presented at AHA 2003
43
SPORTIF V - aumento transaminasiALT gt3 x val.
normale
50
Warfarin
Ximelagatran
40
38
35
30
Numero di pazienti
20
10
10
7
6
4
4
3
3
2
2
2
2
2
2
1
1
1
1
1
1
1
1
1
1
0
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
44
Net Clinical Benefit Primary Events Major
Bleeding DeathOn-treatment Analysis
Event Rate ( /year)
Warfarin
14
Ximelagatran
12
10
RRR 26p0.019
RRR 7p0.527
RRR 16 p0.038
8
6.2
6.3
6.2
5.8
6
5.2
4.6
4
2
0
SPORTIF V
Pooled
SPORTIF III
Halperin JL, Presented at AHA 2003
45
Idraparinux sodium (SanOrg34006) Phase III
Amadeus AF
Patients with AF, eligible for VKA treatment
INR-adjusted VKA
Randomization
2.5 mg idraparinux o.w.
Treatment 6-24 months open-label EFFICACY All
strokes and non-CNS embolism SAFETY All bleeding
46
New anticoagulantsUnmet clinical needs

• More effective and safer agents for VTE
  prophylaxis in high risk surgery (major
  orthopedic and cancer)
• More practical agents for post-discharge
  prophylaxis of VTE
• More practical agents for long-term treatment (no
  monitoring) of VTE
• More practical agents for long-term treatment (no
  monitoring) of atrial fibrillation
• Safer adjunctive treatment for STEMI and ACS
• More effective agents for secondary prophylaxis
  of MI

47

• Randomized, double-blinded, dose-escalation,
  multicenter trial
• 154 pts with stable angina scheduled for elective
  PCI
• All pts treated with ASA, UH, clopidogrel (if
  stent)
• rNAPc2 3.5, 5.0, 7.5 and 10.0 microg/kg or
  placebo as a single sc administration 2-6 h after
  angioplasty
• Registration of minor and major bleeding and F12
  levels as index of thrombin generation

48

all 3 pts treated also with GP IIb-IIIa
inhibitor
49
Femoral compression time after sheath removal
50
Plasma levels of r-NAPc2 in relation to plasma
levels of F12 at 36 hr
Thrombin generation suppressed in all rNAPc2
groups for at least 36 hrs
51
New anticoagulantsUnmet clinical needs

• More effective and safer agents for VTE
  prophylaxis in high risk surgery (major
  orthopedic and cancer)
• More practical agents for post-discharge
  prophylaxis of VTE
• More practical agents for long-term treatment (no
  monitoring) of VTE
• More practical agents for long-term treatment (no
  monitoring) of atrial fibrillation
• Safer adjunctive treatment for STEMI and ACS
• More effective agents for secondary prophylaxis
  of MI

52
Oral ximelagatran for secondary prophylaxis after
myocardial infarction. The ESTEEM randomised
controlled trial

• Wallentin L et al,
• Lancet 2003 362789-97

53
ESTEEM StudyWallentin L et al. Lancet 2003 362
78997

• 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

54
ESTEEM StudyWallentin L et al. Lancet 2003 362
78997
Cumulative risk of death, myocardial infarction,
andstroke. Data are for all ximelagatran doses
pooled. Analysis by intention-to-treat
55
ESTEEM- Emorragie Wallentin L et al. Lancet
2003 362 78997
56
ESTEEM - ConclusioniWallentin L et al, Lancet
2003 362789-97

• Lassociazione ximelagatran-ASA è più efficace
  del solo ASA nella prevenzione di eventi
  cardiovascolari maggiori nei 6 mesi successivi ad
  infarto del miocardio

57
New agents in clinical developmentThe search
for selectivity

TF/VIIa
IX
X
VIIIa
IXa
Xa
Va
II
IIa
i
58
New anticoagulantsUnmet clinical needs

• VENOUS THROMBOEMBOLISM
• More effective and safer agents for prophylaxis
• More practical agents for post-discharge
  prophylaxis
• More practical agents for long-term treatment (no
  monitoring)
• ATRIAL FIBRILLATION
• More practical agents for long-term treatment (no
  monitoring)
• STEMI and ACS
• Safer adjunctive treatment
• MYOCARDIAL INFARCTION
• More effective agents for secondary prevention

59
New anticoagulantsUnmet (?) clinical needs

• VENOUS THROMBOEMBOLISM
• More effective and safer agents for prophylaxis
• More practical agents for post-discharge
  prophylaxis
• More practical agents for long-term treatment (no
  monitoring)
• ATRIAL FIBRILLATION
• More practical agents for long-term treatment (no
  monitoring)
• STEMI and ACS
• Safer adjunctive treatment
• MYOCARDIAL INFARCTION
• More effective agents for secondary prevention