Nuovi farmaci antitrombotici: che cosa cambierà in clinica
nei prossimi anni?GF Gensini
Livorno 27 marzo 2004
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
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
New antithrombotic agents
Factor XFactor X
Factor XaFactor Xa
Prothrombinase Prothrombinase complexcomplex
FibrinogenFibrinogenThrombinThrombin
ProthrombinProthrombin
Selective anti-IIa inhibitorsSelective anti-IIa inhibitors
FIXa-FVIIIa, Phospholipids, Ca++FIXa-FVIIIa, Phospholipids, Ca++
Tissue factor - FVIIaTissue factor - FVIIa
rNAPc2 rNAPc2
PentasaccharidePentasaccharide
Direct anti-Xa inhibitorsDirect anti-Xa inhibitors
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
Adjusted-Dose Warfarin Compared with Placebo
AFASAK I
SPAF
BAATAF
CAFA
SPINAF
EAFT
All trials (n=6) RRR 62% (95% CI 48-72%)
100% 50% 0 - 50% - 100%
Relative Risk Reduction of Stroke (95% CI)
Warfarin Better Warfarin Worse
Hart et al Ann Intern Med 1999; 131: 492-501
All cause mortality decreased
[RRR 26% (4-43)]
Optimal Intensity for Warfarin Therapy
INR Odds Ratio2.0 1.01.7 2.01.5 3.31.3 6.0
1.0 1.5 3.0 4.0 7.0
1
3
5
10
15
INR2.0
Od
ds
Rat
io f
or
Str
oke
N Engl J Med 1996;335:540-546
AFASAK I
SPAF I
EAFT
ESPS II
LASAF
UK-TIA
All trials (n=6) RRR 22% (95% CI 2-38%)
Relative Risk Reduction of Stroke (95% CI)
Aspirin Better Aspirin Worse
Aspirin Compared with Placebo
100% 50% - 50% - 100%0
Hart et al Ann Intern Med 1999; 131: 492-501
All cause mortality
not significantly
decreased
ATRIAL FIBRILLATION INVESTIGATORS
Arch Intern Med 1994
Studio ISCOAT: età come fattore di rischio per emorragia
Età % anni/paz.
< 50 y 6.9
50-69 y 5.6
70 y 10.5
Analisi univariate : 70 y vs < 70 y RR = 1.75 (p<0.001)(da Palareti et al. Lancet 1996)
Safety of OAT in the elderly: a review(Hutton et al. Drugs & Aging 1999)
Conclusions:
• A clear tendency towards >bleeding in elderly
• More evident in studies comparing elderly and younger pts
• The risk is likely underestimated because several trials excluded pts > 75
• Caution is needed in elderly pts; evaluation case-by-case
Complications During Long-Term OAC in 360 Patients With AF Complication All Patients
(n=360) Taking 3 Drugs (n=175)
Taking >3 Drugs(n=185)
Thromboembolic and bleeding events 14.6 4.3 24.4*
Bleeding Total 13.1 3.4 22.2
Minor 5.8 1.7 9.6
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
0.3
0.0
0.5 Fatal
0.2
0.0
0.3
Values are percentage per 100 patient-years. *P=0.0041; P=0.0073; P=0.0356.
Wehinger C, et al. Stroke 2001 32: 2246
Br J Haematol 1998; 101:374 Blood 1999; 94: 3007
Negli anzianiIn pazienti con scompenso cardiaco
In pazienti con epatopatia
12
3
4
Bambini 0.2 mg/kg (W)
dose
Vitamina K >40 μg/100 g INRThromb Haemost 1997; 77: 504Haemostasis 1993; 23 77
riduzione
Vitamina K >40 μg/100 g
INR
Thromb Haemost 1997; 77: 504Haemostasis 1993; 23 77
riduzione
Vitamina K >40 μg/100 g
INR
Thromb Haemost 1997; 77: 504Haemostasis 1993; 23 77
riduzione
Vitamina K
5-40 μg/100 g
NECESSITA’ DI UNA VALUTAZIONE INDIVIDUALE DEL RAPPORTO RISCHIO BENEFICIO DELLA
SCELTA PROFILATTICA
Il cardiologo dovrebbe appoggiare Il cardiologo dovrebbe appoggiare il paziente ad un Centro di il paziente ad un Centro di monitoraggio della TAO ?monitoraggio della TAO ?
02468
10121416
san
gu
inam
ento
% a
nn
o-p
z.
ISCOAT studi osserv. studi sperim.
sanguinamentofatale
sanguinamentomaggiore
sanguinamentominore
** **** Landefeld et al., 1993
Un buon monitoraggio della TAO consente di avere una efficacia ed una sicurezza paragonabili
o migliori di quelle dei trial clinici
02468
10121416
san
gu
inam
ento
% a
nn
o-p
z.
ISCOAT studi osserv. studi sperim.
sanguinamentofatale
sanguinamentomaggiore
sanguinamentominore
** **** Landefeld et al., 1993
Un buon monitoraggio della TAO consente di avere una efficacia ed una sicurezza paragonabili
o migliori di quelle dei trial clinici
0
1
2
3
4
5
6
7
% e
ven
ti p
er a
nn
o-p
z.
prima dopo
sanguinamento
tromboembolia
Eventi clinici prima e dopo arruolamento in Centro Anticoagulati (paz con PVM)
Cortelazzo et al. 1993
Pazienti in trattamento con anticoagulanti orali in Italia*
424692484574
538362650000
1000000
0
200000
400000
600000
800000
1000000
1998 1999 2000 2002 2008
Stima, Clin Cardiol PD 2002
Centri FCSA2003
N=306
Considerazioni al momento di decidere il trattamento con AO
(in particolare in un soggetto di età>75 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
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
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
Stroke Prevention using an ORal Thrombin Inhibitor in
atrial Fibrillation (SPORTIF III)Lancet 2003;362:1691-98
The SPORTIF III StudyThe SPORTIF III Study
•Randomised, parallel group, Randomised, parallel group, open-labelopen-label treatment allocation, blinded event assessment treatment allocation, blinded event assessment
•23 countries, 259 centers23 countries, 259 centers
•Exposure: mean 17 months, 4941 patient-years and 96 primary endpoints.
Adjusted-doseAdjusted-dose
WarfarinWarfarin(INR 2-3)(INR 2-3)
Fixed-doseFixed-dose
ximelagatranximelagatran(36 mg b.i.d.)(36 mg b.i.d.)
Nonvalvular atrial fibrillation patients withNonvalvular atrial fibrillation patients withat least one aditional risk factor for strokeat least one aditional risk factor for stroke
n=3 407n=3 407
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
Non-Inferiority TestingXimelagatran SuperiorXimelagatran Superior Warfarin SuperiorWarfarin Superior
-2%
SuperioritySuperiority
Absolute Difference in Event RatesAbsolute Difference in Event Rates
EquivalenceEquivalence
0% +2%
Non-inferiorityNon-inferiority
Circulation 2003;108:2723
Paragone di vari eventi compositi
SPORTIF III, Lancet 2003;362:1691-98
SPORTIF IIIStroke e/o embolia sistemica
(intention to treat)
p=p=0.100.10
0
1
2
3
4
0 3 6 9 12 15 18 21Durata (mesi)
WarfarinXimelagatran
Eve
nti
cu
mu
lati
vi (
%)
56 eventi (2.3%/anno)
40 eventi (1.6%/anno)
Presented at ACC 2003
4.6%
0
2
4
6
8
10
12
14
Eventi (% per anno)
Eventi primari + emorragie maggiori + morte
6.1%
RRR=25%p = 0.022
Eventi avversi maggiori(on treatment analysis)
XimelagatranWarfarin
Presented at ACC 2003
0246
8101214Eventi (%)
ALT >3x limite sup.
norma
p <0.0016.5%
0.7%
Altri eventi avversiAumento enzimi epatici
XimelagatranWarfarin
Presented at ACC 2003
The SPORTIF V StudyThe 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.
Adjusted-doseAdjusted-dose
WarfarinWarfarin(INR 2-3)(INR 2-3)
Fixed-doseFixed-dose
XimelagatranXimelagatran(36 mg bid)(36 mg bid)
Nonvalvular atrial fibrillation patients withNonvalvular atrial fibrillation patients withat least one aditional risk factor for strokeat least one aditional risk factor for stroke
n=3 922n=3 922
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
SPORTIF V - Stroke ed embolismo sistemico (Intention to treat)
Ximelagatran 1960 1900 1596 848 243Warfarin 1962 1910 1624 867 240Ximelagatran 1960 1900 1596 848 243Warfarin 1962 1910 1624 867 240
Ximelagatran
Warfarin
Mesi
51 events (1.6%/anno)
37 eventis (1.2%/anno)
0 3 6 9 12 15 18 21 24
EventEventi cumulativii cumulativi (%/(%/annoanno))
00
11
22
33
44
55
77
66
pp=0.13=0.13
SPORTIF V - Emorragie (Analisi on treatment)
3.1%
47%
0.1% 0.1% 2.4%
37%
0
10
20
30
40
50
Cerebrali Maggiori Maggiori + minori
WarfarinXimelagatran
Eventi (% /anno)p<0.0001
p=p=0.160.16NS
SPORTIF ProgramStroke and Systemic Embolism
Intention-to-treat Analysis
Months
0 3 6 9 12 15 18 21 24
V
0
1
2
3
4
5
7
6
SPORTIFIII
1.2%/year1.2%/year1.2%/year1.2%/year
WarfarinWarfarin
2.3%/year2.3%/year2.3%/year2.3%/year1.6%/year1.6%/year1.6%/year1.6%/yearXimelagatranXimelagatran
1.6%/year1.6%/year1.6%/year1.6%/year
Halperin JL, Presented at AHA 2003
Cumulative Event Rate (%year)
SPORTIF (Analisi intention to treat)
SPORTIF IIISPORTIF IIISPORTIF IIISPORTIF III
SPORTIF VSPORTIF V
-0.66-0.66
+0.45+0.45
-1.5-1.5 -1-1 -0.5-0.5 00 0.50.5 11 1.51.5 22
Differenza assoluta nella frequenza di eventi(Ximelagatran – Warfarin)
Ximelagatran meglio Warfarin meglio
PooledPooled-0.03-0.03
0%0%
20%20%
40%40%
60%60%
80%80%
100%100%
33 66 99 1212 1515 1818 2121
<1.8<1.8
>3.2>3.2
2.0-3.02.0-3.0
Treatment duration (months)Treatment duration (months)
Tim
e in
ra
ng
e (
%)
66%66% 81%81%
Lancet 2003
SPORTIF IIIINR Values – Warfarin Group
0
20
40
60
80
100
Tim
e in
Ra
ng
e (
%)
83%83%
Treatment Duration (months)
3 6 9 12 15 18 21 24 26
SPORTIF VINR Values – Warfarin Group
>3.2>3.2
<1.8<1.8
Halperin JL, Presented at AHA 2003
68%68%2.0-3.02.0-3.0
SPORTIF ProgramMajor Bleeding
On-treatment Analysis
SPORTIF VSPORTIF V PooledPooledSPORTIF IIISPORTIF III
pp=0.054=0.054
Event Rate (% /year)
3.1%
2.5%
1.8%
1.3%
2.4%
1.9%
XimelagatranXimelagatranWarfarinWarfarin
0
4
3
2
1
Halperin JL, Presented at AHA 2003
0
10
SPORTIF Program ALAT >3X ULN
0.8% 0.8%
6.0% 6.1%6.3%
XimelagatranXimelagatranWarfarinWarfarin
Elevated bilirubin >2 x ULNElevated bilirubin >2 x ULN
Incidence (%)
6
4
2
8
Halperin JL, Presented at AHA 2003
SPORTIF VSPORTIF V PooledPooledSPORTIF IIISPORTIF III
0.8%
SPORTIF V - aumento transaminasiALT >3 x val. normale
13 2 1 1 1 1 2 1 12
38
35
10
7 6
2 24 4
1 2 31 1
0
10
20
30
40
50
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
Warfarin Ximelagatran
Mesi
Nu
mer
o d
i paz
ien
ti
Net Clinical Benefit Primary Events + Major Bleeding + Death
On-treatment Analysis
SPORTIF VSPORTIF V PooledPooledSPORTIF IIISPORTIF III
Event Rate (% /year)
6.2% 6.2%6.3% 5.8% 5.2%4.6%
RRR = 26%p=0.019
RRR = 7%p=0.527
RRR = 16 %p=0.038
XimelagatranXimelagatranWarfarinWarfarin
0
14
12
10
8
6
4
2
Halperin JL, Presented at AHA 2003
Patients with AF, eligible for VKA
treatmentR
ando
miz
atio
n2.5 mg idraparinux o.w.
INR-adjusted VKA
Idraparinux sodium (SanOrg34006) Phase III Amadeus AF
Treatment 6-24 months
open-label
EFFICACY: All strokes and non-CNS embolism
SAFETY: All bleeding
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
•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 F1+2 levels as index of thrombin generation
§
§ all 3 pts treated also with GP IIb-IIIa inhibitor
Femoral compression time after sheath removal
Plasma levels of r-NAPc2 in relation to plasma levels of F1+2 at 36 hr
Thrombin generation suppressed in all rNAPc2 groups for at least 36 hrs
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
Oral ximelagatran for secondary prophylaxis after myocardial infarction.
The ESTEEM randomised controlled trial
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
ESTEEM StudyWallentin L et al. Lancet 2003; 362: 789–97
ESTEEM StudyWallentin L et al. Lancet 2003; 362: 789–97
Cumulative risk of death, myocardial infarction, andstroke. Data are for all ximelagatran doses pooled. Analysis by intention-to-treat
ESTEEM- Emorragie Wallentin L et al. Lancet 2003; 362: 789–97
0
5
10
15
20
25
30
%
maggiori
interr. trattamento
maggiori+minori
ESTEEM - ConclusioniWallentin 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
Thrombin Inhibitors: DS, Hirudin, Bivalirudin, Argatroban,
Melagatran, Ximelagatran
IXa inhibitors Xa inhibitors:
PentasaccharideTAP, Antistasin, DX 9065a, DPC 906
Protein C Activators aPC, Thrombomodulin
Coagulation Pathway Antithrombotics in development
Tissue Factor Pathway InhibitorsTFPI, rNAPc2, VIIa inhibitors
Initiation
Thrombingeneration
Thrombinactivity
TF/VIIa
IIa
II
Xa
IXa
IXX
VIIIa
Va
i
New agents in clinical development:
The search for selectivity
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
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