nuovi farmaci antitrombotici: che cosa cambierà in clinica nei prossimi anni? gf gensini livorno 27...

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

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

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

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

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


0246

8101214Eventi (%)

ALT >3x limite sup.

norma

p <0.0016.5%

0.7%

Altri eventi avversiAumento enzimi epatici

XimelagatranWarfarin


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


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


0

10

SPORTIF Program ALAT >3X ULN

0.8% 0.8%

6.0% 6.1%6.3%


Elevated bilirubin >2 x ULNElevated bilirubin >2 x ULN

Incidence (%)

6

4

2

8



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


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


0

14

12

10

8

6

4

2


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

•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

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


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

nuovi farmaci antitrombotici: che cosa cambierà in clinica nei prossimi anni? gf gensini livorno 27...

Documents

riduzione slide

practical agents

g100 g slide

effective agents

safer agents

vte prophylaxis

monitoring of vte

mgkg w dose slide