RFVIIa: usos cl nicos para manejo del sangrado cr tico.

1. Slide No. 1 � Footer � rFVIIa: usos cl�nicos para manejo del sangrado cr�tico. Servicio de Terapia Intensiva - Hospital de Cl�nicas Montevideo � Uruguay.

2. Slide No. 2 � Footer � rFVIIa en el manejo del sangrado cr�tico Introducci�n Mecanismo de acci�n Uso en hemofilia cong�nita Uso en hemofilia adquirida D�ficit cong�nito de FVII Trombastenia de Glanzmann y trombocitopat�as Nuevas indicaciones (Uso compasivo)

3. Slide No. 3 � Footer � INTRODUCCION 1981 la Dra. Ulla Hedner purifica peque�as cantidades de FVIIa. 1983 se publica el primer trabajo en el J Clin Invest. 1988 primer paciente hemof�lico tratado en forma efectiva en una cirug�a ortop�dica mayor. 1996 aprobaci�n para su uso en Europa. 2000 aprobaci�n para su en Jap�n. 2003 aprobaci�n para su uso en Europa para la Tromboastenia de Glanzmann.

4. Slide No. 4 � Footer � NovoSeven� � Factor recombinante VIIa (rFVIIa)

5. Slide No. 5 � Footer � Comparaci�n de FVIIa recombinante con el FVII plasm�tico.

6. Slide No. 6 � Footer � Mecanismos de acci�n NovoSeven� tiene dos mecanismos de acci�n � Sustituci�n del FVIIa cong�nitamente ausente en la iniciaci�n de la hemostasia. � Derivaci�n (by-pass) de defectos en el proceso normal de coagulaci�n en ciertos pacientes con coagulopat�a.

7. Slide No. 7 � Footer � El sistema hemost�tico Las tres fases Hemostasia primaria: vasoconstricci�n y tap�n plaquetario Hemostasia secundaria: co�gulo de fibrina Fibrin�lisis: lisis del co�gulo

8. Slide No. 8 � Footer � FVIIa en la iniciaci�n de la coagulaci�n

9. Slide No. 9 � Footer � Hemostasia primaria � Formaci�n del trombo plaquetario

10. Slide No. 10 � Footer � Fisiopatolog�a de la hemofilia A

11. Slide No. 11 � Footer �

12. Slide No. 12 � Footer �

13. Slide No. 13 � Footer �

14. Slide No. 14 � Footer � rFVIIa en la hemofilia A con inhibidores

15. Slide No. 15 � Footer � El FVIIa se une a las Plaquetas La baja afinidad de la uni�n del rFVIIa a las plaquetas activadas explica el requerimiento de altas dosis. El hallazgo de que el rFVIIa no se une al resto de las plaquetas explica porqu� no se observa una coagulaci�n sist�mica luego de la utilizaci�n del rFVIIa. FVIIa Binding to Platelets To assess the interaction of FVIIa with platelets, the binding of FVIIa to platelets was examined using indirect immunofluorescence and flow cytometry. The results are shown on this slide. The units of measure in flow cytometry are relative fluorescence. The fluorescence levels from several different experiments were normalized so that binding from several people could be compared. FVIIa did not bind to the unactivated platelets (shown in red), nor did it bind to activated platelets in the absence of calcium (shown in orange). However, in the presence of calcium, FVIIa bound weakly to activated platelets with a half-maximal binding at 100 nM (in contrast to binding to tissue factor [TF], which is half maximal at less than 0.01 nM). Monroe DM et al. Br J Haematol 1997;99:542�547.La baja afinidad de la uni�n del rFVIIa a las plaquetas activadas explica el requerimiento de altas dosis. El hallazgo de que el rFVIIa no se une al resto de las plaquetas explica porqu� no se observa una coagulaci�n sist�mica luego de la utilizaci�n del rFVIIa. FVIIa Binding to Platelets To assess the interaction of FVIIa with platelets, the binding of FVIIa to platelets was examined using indirect immunofluorescence and flow cytometry. The results are shown on this slide. The units of measure in flow cytometry are relative fluorescence. The fluorescence levels from several different experiments were normalized so that binding from several people could be compared. FVIIa did not bind to the unactivated platelets (shown in red), nor did it bind to activated platelets in the absence of calcium (shown in orange). However, in the presence of calcium, FVIIa bound weakly to activated platelets with a half-maximal binding at 100 nM (in contrast to binding to tissue factor [TF], which is half maximal at less than 0.01 nM). Monroe DM et al. Br J Haematol 1997;99:542�547.

16. Slide No. 16 � Footer � � Convierte el fibrin�geno en mon�meros de fibrina � Activa m�s plaquetas y otros factores, amplificando as� adicionalmente el sistema. � Activa el inhibidor de la fibrin�lisis activado por trombina (TAFI) � Activa el factor XIII, que ayuda a estabilizar el co�gulo de fibrina. Hemostasia secundaria � La explosi�n de trombina

17. Slide No. 17 � Footer � Fibrin�lisis � Rutas de la fibrin�lisis

18. Slide No. 18 � Footer � Fibrin�lisis � Equilibrio hemost�tico

19. Slide No. 19 � Footer � Indicaciones autorizadas Hemofilia cong�nita con inhibidores para los factores de coagulaci�n VIII o IX >5 BU o que se espera que tengan una respuesta anamn�sica alta con los factores VIII o IX. Hemofilia adquirida. Deficiencia cong�nita del factor VII. Trombastenia de Glanzmann con anticuerpos contra glucoprote�na GP IIb-IIIa y/� HLA, y con respuestas pasadas o presentes a la transfusi�n de plaquetas.

20. Slide No. 20 � Footer � Hemofilia Cong�nita Hemofilia A: d�ficit de factor VIII Hemofilia B: d�ficit de factor IX 1800 pacientes registrados en el pa�s Con inhibidor aproximadamente 45 pacientes Hemofilia Leve: 5 a 25% Moderada: 1 a 4% Severa: <1%

21. Slide No. 21 � Footer � Hemofilia Cong�nita Inhibidores: Prevalencia: Hemofilia A ~30% (10% a 50%) Hemofilia B 3% a 5% Unidades de medici�n: Unidades Bethesda = UB 1 BU = cantidad de inhibidor que neutraliza el 50% de la actividad del factor luego de 2 h a 37�C. Bajo t�tulo: < 5UB Alto t�tulo: > 5UB The prevalence of inhibitors for persons with severe FVIII deficiency has been estimated to be approximately 30% with a reported range of 10% to 50%. In individuals with severe FIX deficiency, inhibitors are mush less common with a prevalence of approximately 3% to 5%. The presence of an inhibitor is measured in the Bethesda assay and is reported in Bethesda units (BU). One BU is the amount of inhibitor that will result in a loss of 50% of factor activity when the patient�s plasma is incubated with normal plasma for 2 hours at 37? C. The prevalence of inhibitors for persons with severe FVIII deficiency has been estimated to be approximately 30% with a reported range of 10% to 50%. In individuals with severe FIX deficiency, inhibitors are mush less common with a prevalence of approximately 3% to 5%. The presence of an inhibitor is measured in the Bethesda assay and is reported in Bethesda units (BU). One BU is the amount of inhibitor that will result in a loss of 50% of factor activity when the patient�s plasma is incubated with normal plasma for 2 hours at 37? C.

22. Slide No. 22 � Footer � Hemofilia Cong�nita Dosis efectiva: 90 - 120 mcg/kg cada 2-3 horas hasta lograr hemostasia Dosis > 200 mcg/kg puede disminuir la necesidad de dosis repetidas. Kenet et al han utilizado mega dosis de 300 mcg/kg, siendo estas dosis efectivas y seguras.

23. Slide No. 23 � Footer � Hemofilia adquirida Descripci�n Autoanticuerpos contra el factor VIII Se presentan clinicamente con sangrados espont�neos. Generalmente en pacientes a�osos Antecedentes de enfermedades autoinmunes, c�ncer, embarazo, exposici�n a drogas. Incidencia de 1 por millon, por a�o Laboratorio: KPTT prolongado (que no corrige con plasma normal). Niveles del FVIII 1-2%

24. Slide No. 24 � Footer � Hemofilia adquirida Mortalidad del 13 al 22% Objetivos del tratamiento Control del sangrado: rFVIIa � FEIBA � PCCs � FVIIIporcino Eliminar el anticuerpo Se utilizan agentes inmunosupresores (ciclofosfamida, ciclosporina � corticoterapia)solos � en combinaci�n con plasmaf�resis

25. Slide No. 25 � Footer � Hemofilia adquiridaExperiencia con rFVIIa Tratamiento de salvataje: >90% de eficacia Primera l�nea terap�utica: 100% de eficacia NovoSeven en hemofilia adquirida > eficacia que FVIIIp, PCC, PCCa, > seguridad

26. Slide No. 26 � Footer � D�ficit de FVII Alteraci�n hereditaria del sangrado Presenta hemorragias severas cuando los niveles plasm�ticos son <2%. Sangrado en articulaciones, menstruaciones importantes, epistaxis, sangrado despu�s de una cirug�a. Incidencia 2/1000000. Tratamiento: rFVIIa, FVII derivado de plasma, plasma fresco, y PCCs. Dosis recomendada de rFVIIa: 20-30 �g/kg de peso. Eficacia > al 90%. Su uso fue aprobado en Europa por la EMEA en enero de 2004.

27. Slide No. 27 � Footer � Alteraciones plaquetarias Alteraciones de la cantidad de las plaquetas Transplante de Stem Cell Fiebre hemorr�gica � Dengue Alteraciones en la funci�n plaquetaria Trombastenia de Glanzmann S�ndrome de Bernard Soulier Enfermedad de pool de dep�sito

28. Slide No. 28 � Footer � Trombastenia de Glanzmann Alteraci�n cong�nita del sangrado Defecto en receptores espec�ficos de la membrana plaquetaria (GP IIb/IIIa). Incidencia 1/1000000 Las plaquetas pierden la habilidad de agregarse y formar un tap�n hemost�tico. M�s frecuente en la mujer. Edad < 20 a�os. Se caracteriza por epistaxis, sangrado de enc�as, hematomas, mentruaciones abundantes, anemia. Requerimiento transfusional en el 77% de los casos

29. Slide No. 29 � Footer � Trombastenia de Glanzmann 3 Tipos Tipo I: GP IIb/IIIa ausente (<5%) Tipo II: GP IIb/IIIa (5-20%) Variantes (modificaciones cualitativas de la GP IIb/IIIa) Tratamiento convencional: transfusi�n de plaquetas, agentes antifibrinol�ticos, desmopresina Dosis de rFVIIa: 80-120 mcg/kg cada 2 horas hasta lograr hemostasia.

30. Slide No. 30 � Footer � D�ficit de FXI Alteraci�n hereditaria del sangrado Es un des�rden gen�tico frecuente entre la poblaci�n jud�a Ashkenazi. Se diferencia de la hemofilia A y B por no presentar sangrado en articulaciones y m�sculos. No son frecuentes los sangrados espont�neos. Tienen riesgo de sangrado despu�s de una cirug�a Tratamiento convencional: plasma fresco, concentrados plasm�ticos de FXI y desmopresina Existen 4 publicaciones que informan un uso exitoso con NovoSeven en profilaxis quir�rgica y manejo del sangrado

31. Slide No. 31 � Footer � Enfermedad de Von Willebrand � Tipo 3 Alteraci�n hereditaria del sangrado Caracterizada por ausencia parcial o total del factor de von Willebrand El Factor vW transporta al FVIII en el torrente sangu�neo y media la adhesi�n plaquetaria en el sitio de la lesi�n. Ocurre cuando una persona tiene 2 genes defectuosos 6% del total de enfermedad de vW. Tratamiento convencional: Concentrados de FVIII/vW Concentrados de FVIII m�s transfusiones de plaquetas Seis pacientes fueron tratados con rFVIIa con una efectividad del 95%

32. Slide No. 32 � Footer � rFVIIa para reversi�n de la anticoagulaci�n En ratas tratadas con Warfarina, el rFVIIa corrigi� el tiempo de protrombina. En voluntarios sanos, tratados con acenocumarol, la prolongaci�n del RIN (>2) se revirti� con una dosis de rFVIIa con dosis de entre 5 a 320 mcg/kg Dosis < 120 mcg/kg pueden normalizar el RIN por el lapso de 24 horas. rFVIIa result� eficaz a una dosis de 90 mcg/kg para revertir la acci�n de fondaparinux con una normalizaci�n en la generaci�n de trombina por m�s de 6 horas luego de la administraci�n. La incidencia de trombosis result� de un 1-2%

33. Slide No. 33 � Footer � Otras indicaciones (uso compasivo) Sangrado quir�rgico Trauma Hemorragia intracerebral Hemorragia posparto Hepatectom�a Cirug�a card�aca Injuria cerebral

34. Slide No. 34 � Footer � Indicaciones quir�rgicas � Hepatectom�a parcial, � Transplante ortot�pico de h�gado, � Cirug�a card�aca (de adulto e infantil), � Cirug�a de la columna vertebral, y � Cirug�a reconstructora de la pelvis.

35. Slide No. 35 � Footer � Otras situaciones hemorr�gicas Ejemplos de otras situaciones hemorr�gicas cr�ticas son � Hemorragia postransplante de m�dula �sea. � Infecciones v�ricas hemorr�gicas (por ejemplo, dengue). � Hemorragia aguda por varices esof�gicas aguda. � Hemorragia intracerebral. � Lesi�n por traumatismo cerebral. � Hemorragia posparto. � Quemaduras.

36. Slide No. 36 � Footer � Trauma La hemorragia severa es la principal causa de muerte en pacientes traumatizados. El 65% de las muertes ocurre despu�s de la admisi�n en hospitalaria. El traumatismo severo se correlaciona con coagulopat�a pos-traum�tica, acidosis, hipotermia y s�ndrome de transfusiones m�ltiples.

37. Slide No. 37 � Footer � La injuria traum�tica es la principal causa de muerte entre los 5�44 a�os La transfusi�n masiva de GR es una variable de riesgo independiente de morbilidad y mortalidad. El sangrado es la segunda causa de mortalidad en la injuria del SNC La prevenci�n del sangrado, previene la exanguinaci�n, reduce la incidencia de shock y previene la muerte en los pacientes traumatizados. Trauma is highly prevalent in the young, and bleeding episodes associated with traumatic injury are an important cause of mortality. Preventing, or significantly reducing, bleeding following trauma will lead to a reduction in the number of RBC units transfused. This, in turn, will reduce: The incidence of haemodynamic shock The number of transfusion-related complications, such as MOF and ARDS The length of stay in ICU The time spent on mechanical ventilation Trauma is highly prevalent in the young, and bleeding episodes associated with traumatic injury are an important cause of mortality. Preventing, or significantly reducing, bleeding following trauma will lead to a reduction in the number of RBC units transfused. This, in turn, will reduce: The incidence of haemodynamic shock The number of transfusion-related complications, such as MOF and ARDS The length of stay in ICU The time spent on mechanical ventilation

38. Slide No. 38 � Footer � TraumaBoffard et al. J Trauma (2005).

39. Slide No. 39 � Footer � Upon receiving 6 units of RBC within a 4-hour period, eligible patients within each trauma population were equally randomised to receive either placebo or NovoSeven�. Patients receiving a further 2 units of RBC (a total of 8 units of RBC) then received their assigned study medication upon transfusion of the 8th unit of RBC: Three IV injections of NovoSeven� (200, 100 and 100 �g/kg), or Three placebo injections The second and third doses were administered after 1 and 3 hours. During the first 48 hours after administration the following were monitored: transfusion and infusion requirements; adverse events; surgical procedures. During the 30-day follow-up, mortality, time on ventilator, hospitalization data, and serious adverse events including pre-defined critical complications (MOF and acute respiratory distress syndrome [ARDS]) were recorded.Upon receiving 6 units of RBC within a 4-hour period, eligible patients within each trauma population were equally randomised to receive either placebo or NovoSeven�. Patients receiving a further 2 units of RBC (a total of 8 units of RBC) then received their assigned study medication upon transfusion of the 8th unit of RBC: Three IV injections of NovoSeven� (200, 100 and 100 �g/kg), or Three placebo injections The second and third doses were administered after 1 and 3 hours. During the first 48 hours after administration the following were monitored: transfusion and infusion requirements; adverse events; surgical procedures. During the 30-day follow-up, mortality, time on ventilator, hospitalization data, and serious adverse events including pre-defined critical complications (MOF and acute respiratory distress syndrome [ARDS]) were recorded.

40. Slide No. 40 � Footer � Boffard et al. J Trauma (2005). Variable de an�lisis primaria: N�mero de unidades de GR transfundidas dentro de las 48hs de administrado el rFVIIa. Resultados de la terapia: N�mero de transfusiones de otros hemoderivados, mortalidad, d�as en respirador y d�as en UTI. Evaluaci�n de la seguridad

41. Slide No. 41 � Footer � As would be expected, most of the blunt trauma was due to motor vehicle accidents and falls. As would be expected, most of the blunt trauma was due to motor vehicle accidents and falls.

42. Slide No. 42 � Footer � Penetrating trauma was mostly due to gunshot wounds and stab wounds and was predominantly in males. Penetrating trauma was mostly due to gunshot wounds and stab wounds and was predominantly in males.

43. Slide No. 43 � Footer � Treatment with NovoSeven� produced a significant reduction in RBC requirements over 48 hours in patients surviving >48 hours (p=0.019). However, a statistically significant haemostatic effect for NovoSeven� treatment was observed at 12 hours (p=0.008) and at 24 hours (p=0.018) following the initial treatment dose. This effect was supported by observations of significant reductions in the transfusion rate in patients treated with NovoSeven� relative to placebo (0.26 units/hour versus 0.37 units/hour, p=0.036).Treatment with NovoSeven� produced a significant reduction in RBC requirements over 48 hours in patients surviving >48 hours (p=0.019). However, a statistically significant haemostatic effect for NovoSeven� treatment was observed at 12 hours (p=0.008) and at 24 hours (p=0.018) following the initial treatment dose. This effect was supported by observations of significant reductions in the transfusion rate in patients treated with NovoSeven� relative to placebo (0.26 units/hour versus 0.37 units/hour, p=0.036).

44. Slide No. 44 � Footer � Administration of NovoSeven� significantly reduced the need for massive transfusions by 56% (95% CI: [9%; 79%]; p=0.03) in the first 48 hours after administration in the blunt trauma group. The need for massive transfusion in penetrating trauma patients was reduced by 63% (95% CI: [-12%; 88%]; p= 0.08). The importance of reducing massive transfusions has recently been demonstrated. A retrospective study has shown that mortality is significantly correlated with the amount of RBC transfused:1 In 5645 acute trauma patients: 479/5645 (8%) patients received RBCs In patients receiving 11 to 20 units RBCs mortality was 30% In patients receiving >20 units RBCs, mortality rose significantly to >50% This effect was independent of severity of injury 1Como JJ et al. Transfusion 2004;44:809-13. Administration of NovoSeven� significantly reduced the need for massive transfusions by 56% (95% CI: [9%; 79%]; p=0.03) in the first 48 hours after administration in the blunt trauma group. The need for massive transfusion in penetrating trauma patients was reduced by 63% (95% CI: [-12%; 88%]; p= 0.08). The importance of reducing massive transfusions has recently been demonstrated. A retrospective study has shown that mortality is significantly correlated with the amount of RBC transfused:1 In 5645 acute trauma patients: 479/5645 (8%) patients received RBCs In patients receiving 11 to 20 units RBCs mortality was 30% In patients receiving >20 units RBCs, mortality rose significantly to >50% This effect was independent of severity of injury 1Como JJ et al. Transfusion 2004;44:809-13.

45. Slide No. 45 � Footer � Further support for the haemostatic effect of NovoSeven� came from significant reductions in both FFP (p=0.036) and platelets (p=0.023) relative to placebo in blunt trauma patients who survived 48 hours or more. The requirement for cryoprecipitate in patients treated with NovoSeven� showed a trend towards reduction relative to placebo (p=0.053). Further support for the haemostatic effect of NovoSeven� came from significant reductions in both FFP (p=0.036) and platelets (p=0.023) relative to placebo in blunt trauma patients who survived 48 hours or more. The requirement for cryoprecipitate in patients treated with NovoSeven� showed a trend towards reduction relative to placebo (p=0.053).

46. Slide No. 46 � Footer � The results from this randomised, double-blind, placebo controlled, parallel group study demonstrate a significant advance in the treatment of critically bleeding, severely ill trauma patients. NovoSeven� significantly reduced the need for transfusion in patients with blunt trauma injuries after they have already received eight units of red blood cells. There was also a significant reduction in the need for massive transfusions. The results from this randomised, double-blind, placebo controlled, parallel group study demonstrate a significant advance in the treatment of critically bleeding, severely ill trauma patients. NovoSeven� significantly reduced the need for transfusion in patients with blunt trauma injuries after they have already received eight units of red blood cells. There was also a significant reduction in the need for massive transfusions.

47. Slide No. 47 � Footer � Hemorragia intracerebral (HIC) Factores de riesgo: Hipertensi�n arterial Terapia anticoagulante oral Otras causas: Sangrado de tumor cerebral Abuso de drogas Alteraciones del sangrado En el 2001, 150.000 sufrieron HIC en el mundo desarrollado

48. Slide No. 48 � Footer � HICMayer et al. N Engl J Med. (2005).

49. Slide No. 49 � Footer �

50. Slide No. 50 � Footer � Patients were enrolled from August 2002 through March 2004 at 73 hospitals in 20 countries. Patients were enrolled from August 2002 through March 2004 at 73 hospitals in 20 countries.

51. Slide No. 51 � Footer � Subjects in whom spontaneous ICH was confirmed by CT scanning within 3 hours of symptom onset were eligible for enrollment and were treated within 1 hour of the baseline scan.Subjects in whom spontaneous ICH was confirmed by CT scanning within 3 hours of symptom onset were eligible for enrollment and were treated within 1 hour of the baseline scan.

52. Slide No. 52 � Footer � Of the 400 randomized patients, 1 subsequently withdrew consent, leaving 399 patients for analysis. Baseline characteristics were similar across groups and representative of what is known from the literature. There were 96, 108, 92, and 103 patients in the placebo, 40 ?g/kg, 80 ?g/kg, and 160 ?g/kg treatment arms, respectively. The mean age was 66 years; 61% were male, and most of the patients were white. The mean ICH volume at baseline (24 mL; range, 0.4 to 153 mL) was similar in the 4 groups. 70% of the patients were treated within a 3-hour time period. The timing of treatment was similar in the 4 treatment groups.Of the 400 randomized patients, 1 subsequently withdrew consent, leaving 399 patients for analysis. Baseline characteristics were similar across groups and representative of what is known from the literature. There were 96, 108, 92, and 103 patients in the placebo, 40 ?g/kg, 80 ?g/kg, and 160 ?g/kg treatment arms, respectively. The mean age was 66 years; 61% were male, and most of the patients were white. The mean ICH volume at baseline (24 mL; range, 0.4 to 153 mL) was similar in the 4 groups. 70% of the patients were treated within a 3-hour time period. The timing of treatment was similar in the 4 treatment groups.

53. Slide No. 53 � Footer � Total Intracranial Blood Volume (ICH + IVH Volume) [not shown] The treatment effect was similar (P for trend = 0.0156 [ICTR value]; P for trend = 0.02 [NEJM value]) for hemorrhages with extension into the ventricles. The combined rFVIIa groups showed significant reduction in ICH + intraventricular hemorrhage (IVH) volume compared to placebo (P = 0.006 [NEJM value]).Total Intracranial Blood Volume (ICH + IVH Volume) [not shown] The treatment effect was similar (P for trend = 0.0156 [ICTR value]; P for trend = 0.02 [NEJM value]) for hemorrhages with extension into the ventricles. The combined rFVIIa groups showed significant reduction in ICH + intraventricular hemorrhage (IVH) volume compared to placebo (P = 0.006 [NEJM value]).

54. Slide No. 54 � Footer � The trial showed a statistically significant reduction (38% relative reduction) in mortality for the combined rFVIIa groups compared to placebo (P = 0.025, chi-square test [ICTR value]; P = 0.02 [NEJM value]). The use of the combination of death and severe disability as a single category made it unlikely that decisions to withdraw life support influenced the results.The trial showed a statistically significant reduction (38% relative reduction) in mortality for the combined rFVIIa groups compared to placebo (P = 0.025, chi-square test [ICTR value]; P = 0.02 [NEJM value]). The use of the combination of death and severe disability as a single category made it unlikely that decisions to withdraw life support influenced the results.

55. Slide No. 55 � Footer � Scores of 0 to 1 on the mRS, 7 to 8 on the E-GOS, 95 to 100 on the Barthel Index, and 0 to 1 on the NIHSS indicated a favorable outcome. Percentages may not total 100 because of rounding off. Twenty patients (5%) were alive but lacked complete outcome data and thus had some or all scores at day 15 carried forward.Scores of 0 to 1 on the mRS, 7 to 8 on the E-GOS, 95 to 100 on the Barthel Index, and 0 to 1 on the NIHSS indicated a favorable outcome. Percentages may not total 100 because of rounding off. Twenty patients (5%) were alive but lacked complete outcome data and thus had some or all scores at day 15 carried forward.

56. Slide No. 56 � Footer � In total, 23 patients experienced 26 serious thromboembolic events. There appeared to be more thromboembolic SAEs in the actively treated groups (7%) compared to placebo (2%); however, the difference was not statistically significant (P = 0.12, Fisher�s exact test). In total, 23 patients experienced 26 serious thromboembolic events. There appeared to be more thromboembolic SAEs in the actively treated groups (7%) compared to placebo (2%); however, the difference was not statistically significant (P = 0.12, Fisher�s exact test).

57. Slide No. 57 � Footer � The use of rFVIIa offers hope for a future treatment of acute ICH�an area where there is currently very little opportunity to actively intervene. Available medical options have been shown to have limited success. The role of surgical treatment of ICH remains controversial.1 It is possible that the use of an agent such as rFVIIa may enhance the safety of early surgical evacuation of haematomas.1,2 rFVIIa appears not only to limit haematoma growth and reduce mortality but also to improve functional outcomes. Thus, more patients receiving the treatment survive and are functionally more independent than patients receiving placebo.3 Until further safety and efficacy data are available, rFVIIa should be used with caution in patients with ICH who have risk factors for thromboembolic disease. More research is required to identify such patients and to determine the optimal therapeutic window. More data are also needed regarding the potential use of rFVIIa for management of patients with ICH related to anticoagulant therapy.3 Morgenstern LB et al. Neurology. 2001;56:1294-1299. Brown DL et al. N Engl J Med. 2005;352:828-830. Mayer SA et a. N Engl J Med. 2005;352:777-785.The use of rFVIIa offers hope for a future treatment of acute ICH�an area where there is currently very little opportunity to actively intervene. Available medical options have been shown to have limited success. The role of surgical treatment of ICH remains controversial.1 It is possible that the use of an agent such as rFVIIa may enhance the safety of early surgical evacuation of haematomas.1,2 rFVIIa appears not only to limit haematoma growth and reduce mortality but also to improve functional outcomes. Thus, more patients receiving the treatment survive and are functionally more independent than patients receiving placebo.3 Until further safety and efficacy data are available, rFVIIa should be used with caution in patients with ICH who have risk factors for thromboembolic disease. More research is required to identify such patients and to determine the optimal therapeutic window. More data are also needed regarding the potential use of rFVIIa for management of patients with ICH related to anticoagulant therapy.3 Morgenstern LB et al. Neurology. 2001;56:1294-1299. Brown DL et al. N Engl J Med. 2005;352:828-830. Mayer SA et a. N Engl J Med. 2005;352:777-785.

58. Slide No. 58 � Footer � Hemorragia Posparto

59. Slide No. 59 � Footer � Hemorragia Posparto En 11 mujeres se obtuvo una respuesta parcial o satisfactoria con el uso de rFVIIa. En 1 paciente no se obtuvo respuesta. En 4 pacientes que fueron sometidas a embolizaci�n arterial, hubo una disminuci�n significativa del sangrado pero no se detuvo en forma completa. El uso de rFVIIa puede ser beneficioso en el tratamiento de la hemorragia posparto con riesgo de vida

60. Slide No. 60 � Footer � Cirug�a Cardiaca

61. Slide No. 61 � Footer � El uso de rFVIIa redujo en forma significativa el uso de transfusiones, Diprose et al, Br J Anaesth, Sept 2005. El uso de rFVIIa como terapia de rescate es efectivo en lograr la hemostasia, prevenir la reexploraci�n quir�rgica y en la reducci�n de los requerimientos transfusionales. Halkos et al, Ann Thorac Surg 2005; 79: 1303-6. El uso tard�o de rFVIIa result� seguro pero no incremento la eficacia respecto de la terap�utica hemost�tica convencional. Von Heymann et al, Crit Care Med, 2005; 33:2241-46. Cirug�a Cardiaca

62. Slide No. 62 � Footer � Hemorragia variceal esof�gica aguda

63. Slide No. 63 � Footer � Hemorragia variceal esof�gica aguda El rFVIIa corrige el tiempo de protrombina en los pacientes cirr�ticos. No se observaron diferencias significativas respecto al tratamiento standard en la poblaci�n general. El rFVIIa disminuye en forma significativa el n�mero de fallas y el control de sangrado a las 24 horas en el subgrupo Child B y C con varices esof�gicas. No hubo diferencias respecto a placebo en la mortalidad a 5 o 42 d�as. No hubo diferencias significativas en la incidencia de efectos adversos inclusive eventos tromboemb�licos respecto a placebo.

64. Slide No. 64 � Footer � Cirug�a Prost�tica

65. Slide No. 65 � Footer � Estudio doble ciego, randomizado controlado contra placebo. Pacientes sometidos a prostactetom�a retrop�bica. Dosis 20 y 40 mcg/kg versus placebo. Perdida sangu�nea promedio: 20 mcg/kg: 1235 mL 40 mcg/kg: 1089 mL p=0.001 Placebo: 2688 mL Ning�n paciente del grupo de 40 mcg/kg (16 pacientes) requirieron transfusiones. Siendo la diferencia significativa de ambos grupos respecto a placebo. No se observaron efectos adversos (el riesgo est�ndar de trombosis venosa es del 2-4% en esta cirug�a) Cirug�a Prost�tica