Nuovi farmaci antitrombotici: che cosa cambierà in clinica nei prossimi anni? GF Gensini Livorno 27 marzo 2004.

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 anticoagulants Unmet 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

Prothrombinase complex
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

All cause mortality decreased
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 (n=6) RRR 62% (95% CI 48-72%) 100% 50% - 50% - 100% Warfarin Better Warfarin Worse Hart et al Ann Intern Med 1999; 131:

Optimal Intensity for Warfarin Therapy
15 INR Odds Ratio 10 Odds Ratio for Stroke 5 3 1 Recently, Hylek et al, evaluated the efficacy of different intensities of anticoagulation in a case-control study. They found that an intensity of anticoagulation below an INR of 2.0 was associated with a higher risk of stroke. 1.0 1.5 2.0 3.0 4.0 7.0 INR N Engl J Med 1996;335:

All cause mortality not significantly decreased
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 All trials (n=6) RRR 22% (95% CI 2-38%) 100% 50% - 50% - 100% Aspirin Better Aspirin Worse Hart et al Ann Intern Med 1999; 131:

ATRIAL FIBRILLATION INVESTIGATORS
Arch Intern Med 1994

Studio ISCOAT: età come fattore di rischio per emorragia
% 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)

Bleeding Thromboembolism
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 0.0 0.3 0.5 Fatal 0.2 0.0 0.3 Values are percentage per 100 patient-years. *P=0.0041; P=0.0073; P= Wehinger C, et al. Stroke : 2246

Negli anziani warfarin 5 mg o meno 1 2
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; 101:374 Blood 1999; 94: 3007

Assunzione irregolare di
broccoli e cavoli Vitamina K >40 μg/100 g INR Thromb Haemost 1997; 77: 504 Haemostasis 1993; 23 77 riduzione

lattuga Vitamina K >40 μg/100 g INR riduzione Thromb Haemost 1997; 77: 504 Haemostasis 1993; 23 77

Assunzione irregolare di spinaci
Vitamina K >40 μg/100 g INR riduzione Thromb Haemost 1997; 77: 504 Haemostasis 1993; 23 77

fagiolini e carote Vitamina K 5-40 μg/100 g

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 ?

Un buon monitoraggio della TAO consente di avere una efficacia ed una sicurezza paragonabili o migliori di quelle dei trial clinici ** ** ** Landefeld et al., 1993

Eventi clinici prima e dopo arruolamento
in Centro Anticoagulati (paz con PVM) Cortelazzo et al. 1993

Pazienti in trattamento con anticoagulanti orali in Italia*
Il calcolo del numero dei pazienti è stato fatto come segue: le ditte produttrici dei farmaci anticoagulanti orali in Italia ci hanno fornito i dati di vendita relativi agli anni 1998,1999,2000. Sulla base delle confezioni vendute siamo risaliti al numero di compresse. Da qui mediante il dosaggio medio settimanale impiegato dai pazienti nel nostro Centro e cioè 28mg/sett per il Coumadin ., 17mg/sett per il Sintrom da 4 mg e 4mg/sett per il Sintrom da 1 mg siamo risaliti al numero di soggetti in terapia anticoagulante ammesso che tutti assumano la terapia per tutto l’anno: Abbiamo poi ipotizzato che un quarto dei pazienti assumano il trattamento per un periodo limitato (4mesi) ed il numero di pazienti in terapia per un periodo limitato è risultato più in terapia cronica= I pazienti intrattamento con Sintrom sono il 32% del totale. Stima, Clin Cardiol PD 2002

Centri FCSA 2003 N=306 I Centri FCSA sono distribuiti in tutto il territorio nazionale in maniera abbastanza omogenea. Sono infatti aumentati negli ultimi anni i Centri nel Sud e nelle isole.

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:

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

Non-Inferiority Testing
Ximelagatran Superior Warfarin Superior Superiority Non-inferiority Equivalence 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 between the two treatment groups. The choice of this margin was based on the event rate in previous trials comparing warfarin to placebo and on the difference in rates considered clinically meaningful. This noninferiority criterion distinguishes the SPORTIF trials from others designed to establish superiority or equivalence compared to an active control. -2% 0% +2% Absolute Difference in Event Rates Circulation 2003;108:2723

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

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

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

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

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

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

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

SPORTIF Program Stroke and Systemic Embolism Intention-to-treat Analysis
Cumulative Event Rate (%year) 7 SPORTIF III V 6 1.2%/year Warfarin 2.3%/year 5 1.6%/year Ximelagatran 4 3 2 When both the SPORTIF III and V trials are considered together, ximelagatran is consistently associated with a low rate of thromboembolism, 1·6% per year. In patients assigned to warfarin, the point estimate for 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 is not clear, but patient, laboratory or other clinical factors may be responsible, or simply the play of chance. 1 3 6 9 12 15 18 21 24 Months Halperin JL, Presented at AHA 2003

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)

SPORTIF III INR Values – Warfarin Group
100% >3.2 80% 60% 66% 81% Time in range (%) 40% 20% The intensity of warfarin anticoagulation was assiduously maintained throughout the study. The mean INR was 2.5 across all measurements over the course of the study. INR values fell within the intended therapeutic range for 66% of the entire duration of exposure and values were within the extended range of 1.8 to 3.2 over 80% of the time, a rate much better than in most published literature or experience in clinical practice. In patients receiving ximelagatran, compliance estimated by pill counts was 94%. <1.8 0% 3 6 9 12 15 18 21 Treatment duration (months) Lancet 2003

SPORTIF V INR Values – Warfarin Group
20 40 60 80 100 >3.2 68% 83% Time in Range (%) In the group assigned to warfarin, the mean INR was 2·4 across all measurements taken over the course of the study. Anticoagulation intensity fell within the target range for 68% of the entire follow-up period and 83% of the time was within the extended range of 1·8 to 3·2. This high quality of anticoagulation control with warfarin is seldom achieved in clinical practice but quite comparable to performance in the open-label SPORTIF III trial. <1.8 Treatment Duration (months) 3 6 9 12 15 18 21 24 26 Halperin JL, Presented at AHA 2003

SPORTIF Program Major Bleeding On-treatment Analysis
Event Rate (% /year) 4 Warfarin 3.1% p=0.054 Ximelagatran 3 2.4% 2.5% 1.9% 2 1.8% 1.3% 1 the findings in SPORTIF V parallel those in SPORTIF III. When the two trials are viewed together, the difference in major bleeding approaches, but does not achieve, statistical significance. SPORTIF III SPORTIF V Pooled Halperin JL, Presented at AHA 2003

SPORTIF Program ALAT >3X ULN
Incidence (%) Warfarin 10 Elevated bilirubin >2 x ULN Ximelagatran 8 6.3% 6.0% 6.1% 6 4 The incidence of ALAT elevations is about the same in both of the large SPORTIF trials. As seen in SPORTIF III, serum bilirubin levels rose above twice the upper limit of normal in a small number of those with transaminase elevations in each treatment group. In SPORTIF V, there were 9 such cases in those assigned to ximelagatran and 1 on warfarin. Based on the global experience and information available from trials of ximelagatran in other thromboembolic disease states, surveillance of serum enzyme activity seems appropriate during the early months of treatment. 2 0.8% 0.8% 0.8% SPORTIF III SPORTIF V Pooled Halperin JL, Presented at AHA 2003

SPORTIF V - aumento transaminasi ALT >3 x val. normale
50 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

Net Clinical Benefit Primary Events + Major Bleeding + Death On-treatment Analysis
Event Rate (% /year) Warfarin 14 Ximelagatran 12 10 RRR = 26% p=0.019 RRR = 7% p=0.527 RRR = 16 % p=0.038 8 6.2% 6.3% 6.2% 5.8% 6 5.2% 4.6% 4 One way to assess the net clinical benefit of treatment with ximelagatran instead of warfarin is to compare the combined rates of the primary endpoints, major bleeding and death. These are similar for both treatment groups in the SPORTIF V cohort, but pooling the data from the two studies yields a statistically significant reduction favoring ximelagatran. 2 SPORTIF III SPORTIF V Pooled Halperin JL, Presented at AHA 2003

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

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

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

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

ESTEEM Study Wallentin L et al. Lancet 2003; 362: 789–97
Cumulative risk of death, myocardial infarction, and stroke. Data are for all ximelagatran doses pooled. Analysis by intention-to-treat

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

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

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

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 STEMI and ACS Safer adjunctive treatment MYOCARDIAL INFARCTION More effective agents for secondary prevention

New anticoagulants Unmet (?) 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 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 marzo 2004.

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Nuovi farmaci antitrombotici: che cosa cambierà in clinica nei prossimi anni? GF Gensini Livorno 27 marzo 2004.

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Presentation on theme: "Nuovi farmaci antitrombotici: che cosa cambierà in clinica nei prossimi anni? GF Gensini Livorno 27 marzo 2004."— Presentation transcript:

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