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REKOMBINOVANI AKTIVIRANI FAKTOR VII NovoSeven

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REKOMBINOVANI AKTIVIRANI FAKTOR VII NovoSeven

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    1. REKOMBINOVANI AKTIVIRANI FAKTOR VII (NovoSeven®) Jovan P. Antovic MD, PhD, Medical Advisor Novo Nordisk A/S ROSEE Ljubljana, Slovenia

    2. od terapije krvarenja u pacijenata sa ihibitorima u hemofiliji, preko uticaja na razumevanje mehanizama hemostaze do potencijalno univerzalnog hemostatskog agensa …

    3. Slide No. 3 • Jovan P Antovic NovoSeven • 12-Nov-05 NovoSeven®

    4. Slide No. 4 • Jovan P Antovic NovoSeven • 12-Nov-05

    5. Slide No. 5 • Jovan P Antovic NovoSeven • 12-Nov-05 NovoSeven® indikacije

    6. Slide No. 6 • Jovan P Antovic NovoSeven • 12-Nov-05 NovoSeven® doziranje i nacin primene

    7. Slide No. 7 • Jovan P Antovic NovoSeven • 12-Nov-05 NovoSeven® upozorenja i monitoring

    8. Slide No. 8 • Jovan P Antovic NovoSeven • 12-Nov-05

    9. Slide No. 9 • Jovan P Antovic NovoSeven • 12-Nov-05 NovoSeven® mehanizam dejstva

    10. Slide No. 10 • Jovan P Antovic NovoSeven • 12-Nov-05

    11. Slide No. 11 • Jovan P Antovic NovoSeven • 12-Nov-05

    12. Slide No. 12 • Jovan P Antovic NovoSeven • 12-Nov-05

    13. Slide No. 13 • Jovan P Antovic NovoSeven • 12-Nov-05

    14. Slide No. 14 • Jovan P Antovic NovoSeven • 12-Nov-05

    15. Slide No. 15 • Jovan P Antovic NovoSeven • 12-Nov-05

    16. Slide No. 16 • Jovan P Antovic NovoSeven • 12-Nov-05 NovoSeven® upotrebljen u 1030 pacijenata opisanih u preko 170 “peer-review” clanaka: Hemofilija 659 pacijenata, 2836 epizoda, efikasnost 82% uz manje od 1% ozbiljnih neželjenih dejstava Druge koagulopatije 260 pacijenata (63 clanka) Oboljenja jetre 132 pacijenta (23 clanka), efikasnost 96% Trombocitopenija/trombocitopatija 45 pacijenata (21 clanak), efikasnost 80% OAT (varfarin) 77 pacijent (15 clanaka), efikasnost 100% Bez prisustva prethodog poremecaja koagulacije 111 pacijenata (40 clanaka), efikasnost 93%, ozbiljna neželjena dejstva kod 2%

    17. Slide No. 17 • Jovan P Antovic NovoSeven • 12-Nov-05 Preko 1100 upotrebe NovoSeven® u registru: www.haemostasis.com Trauma: 657 Trombocitopenija: 211 Kardiotorakalne intervencije: 162 Urodjeni poremecaji trombocita 39 Obstetricija/Ginekologija: 59 Hiruška i posthiruška krvarenja: 835 (abdominalna, neurohiruška, ortopedska, vaskularna, ostalo) Spontana nehiruška krvarenja: 318 (u cns, dentalna, gastrointestinalna, gastrointestinalna sa varikozitetima, mišicnoskeletna, plucna hemoragija, druga respiratorna ukljucujuci i hemoptizije, urološka, ostalo)

    18. Slide No. 18 • Jovan P Antovic NovoSeven • 12-Nov-05

    19. Slide No. 19 • Jovan P Antovic NovoSeven • 12-Nov-05 TRAUMA

    20. Slide No. 20 • Jovan P Antovic NovoSeven • 12-Nov-05 TRAUMA

    21. Slide No. 21 • Jovan P Antovic NovoSeven • 12-Nov-05

    22. Slide No. 22 • Jovan P Antovic NovoSeven • 12-Nov-05 Krvarenje je vodeci uzrok akutne smrti u traumi* The results presented here are based on a study of the causes of death in 289 trauma patients in Denver, Colorado in 1992: Predominant causes of trauma were: Gunshot wounds (42%); road traffic accidents (38%); and, falls (8%) Mean age was 36.8±1.2 years Mean injury severity score was 35.7±1.2. Haemorrhage leading to exsanguination is the most common cause of death following trauma during the first 48 hours in patients transported to the hospital Exsanguination was the most frequent cause of the acute deaths (51%), 72 (92%) of these 78 patients had severe isolated or combinated injuries of the liver (n = 30), heart (n = 28), and major vessels (n = 24). Forty-six (59%) of these were caused by penetrating injuries (39% or 85% were GSWs). Central nervous system injuries were the second most frequent cause of acute deaths, and these occurred as a result of isolated or combinated brain lacerations (n = 23), brain contusions (n = 25), and subdural hematomas (n = 24). Gunshot wounds caused 43% of these acute CNS-related deaths in 43%. 51% of patients who reached hospital and who died withing 48 hours, died as a result of exsanguination.The results presented here are based on a study of the causes of death in 289 trauma patients in Denver, Colorado in 1992: Predominant causes of trauma were: Gunshot wounds (42%); road traffic accidents (38%); and, falls (8%) Mean age was 36.8±1.2 years Mean injury severity score was 35.7±1.2. Haemorrhage leading to exsanguination is the most common cause of death following trauma during the first 48 hours in patients transported to the hospital Exsanguination was the most frequent cause of the acute deaths (51%), 72 (92%) of these 78 patients had severe isolated or combinated injuries of the liver (n = 30), heart (n = 28), and major vessels (n = 24). Forty-six (59%) of these were caused by penetrating injuries (39% or 85% were GSWs). Central nervous system injuries were the second most frequent cause of acute deaths, and these occurred as a result of isolated or combinated brain lacerations (n = 23), brain contusions (n = 25), and subdural hematomas (n = 24). Gunshot wounds caused 43% of these acute CNS-related deaths in 43%. 51% of patients who reached hospital and who died withing 48 hours, died as a result of exsanguination.

    23. Slide No. 23 • Jovan P Antovic NovoSeven • 12-Nov-05 Koagulopatija je vodeci uzrok smrtnosti vezane za krvarenja u traumi Poremecaj zgrušavanja je uzrokovan: Potrošnom koagulopatijom: Faktori koagulacije se troše usled formiranja ugruška Diluciona koagulopatija: Nadoknada tecnosti dovodi do dilucije faktora koagulacije i trombocita, a i remeti njihovu funkciju Hipotermija: Inhibira faktore koagulacije i funkciju trombocita. Usporava stvaranje fibrina Metabolicki poremecaji: Acidoza i hipokalcemija su uobicajene u šoku. Oba poremecaja dovode do poremecaja zgrušavanja Coagulopathy is the major cause of bleeding-related mortality in trauma patients who survive the operating room. It is associated with hypothermia and acidosis, forming the so-called ‘lethal triad’. Factors contributing to post-traumatic coagulopathy, include: Depletion of clotting factors as a result of attempts to form clots at multiple injury sites Dilution of endogenous clotting factors resulting from fluid resuscitation and/or transfusions Reduced platelet function and prolonged bleeding times resulting from hypothermia, acidosis and hypocalcaemia – common complications in severely bleeding trauma patients. Coagulopathy is the major cause of bleeding-related mortality in trauma patients who survive the operating room. It is associated with hypothermia and acidosis, forming the so-called ‘lethal triad’. Factors contributing to post-traumatic coagulopathy, include: Depletion of clotting factors as a result of attempts to form clots at multiple injury sites Dilution of endogenous clotting factors resulting from fluid resuscitation and/or transfusions Reduced platelet function and prolonged bleeding times resulting from hypothermia, acidosis and hypocalcaemia – common complications in severely bleeding trauma patients.

    24. Slide No. 24 • Jovan P Antovic NovoSeven • 12-Nov-05 Serija od 81 pacijenta sa akutnom koagulopatijom koja nije odgovarala na suportivnu terapiju. 46 akutnih traumatskih hemoragija povreda glave, warfarin, steceni defekti, FVII deficijencija PT se skratilo u 78/78 pacijenata nakon rFVIIa. 61/81 pacijenata je odgovorilo na terapiju sa rFVIIa. 34/61 od njih je preživelo i otpušteno (17 pacijenata je umrlo od povreda glave i 10 od MOF) Nije bilo dokaza tromboza. rFVIIa uspešno koriguje stecenu koagulopatiju

    25. Slide No. 25 • Jovan P Antovic NovoSeven • 12-Nov-05 Davanje rFVIIa smanjuje potrošnju krvnih derivata Potrošnja derivata krvi je ispitivana kod 61 pacijenta koji su kvalifikovani kao “responderi” na terapiju. Potrošnja RBC, plazme, kao i ukupno derivata krvi je znacajno (* p<0.0001) smanjena 24 casa nakon rFVIIa u poredjenju sa 24 casa pre tretmana.

    26. Slide No. 26 • Jovan P Antovic NovoSeven • 12-Nov-05 Martinowitz et al. Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force J Thromb Haemost 2005; 3: 640-8.

    27. Slide No. 27 • Jovan P Antovic NovoSeven • 12-Nov-05 Martinowitz et al. Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force J Thromb Haemost 2005; 3: 640-8.

    28. Slide No. 28 • Jovan P Antovic NovoSeven • 12-Nov-05 Martinowitz et al. Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force J Thromb Haemost 2005; 3: 640-8.

    29. Slide No. 29 • Jovan P Antovic NovoSeven • 12-Nov-05 Martinowitz et al. Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force J Thromb Haemost 2005; 3: 640-8. Zaustavljanje krvarenja kod 72% (26/36) Preživljavanje 61% (22/36)

    30. Slide No. 30 • Jovan P Antovic NovoSeven • 12-Nov-05

    31. Slide No. 31 • Jovan P Antovic NovoSeven • 12-Nov-05 Studija 2159: Potrebe za RBC u toku 48-casovnog posmatranja nakon prve doze

    32. Slide No. 32 • Jovan P Antovic NovoSeven • 12-Nov-05 Studija 2159: Potrebe za masivnim transfuzijama* u prvih 48 casova† Administration of rFVIIa 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 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 rFVIIa 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 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.

    33. Slide No. 33 • Jovan P Antovic NovoSeven • 12-Nov-05 Studija 2159: Potrebe za FFP, trombocitima i krioprecipitatom u prvih 48 casova – blunt trauma*

    34. Slide No. 34 • Jovan P Antovic NovoSeven • 12-Nov-05 Studija 2159: ARDS i MOF u okviru 30 dana - blunt trauma†

    35. Slide No. 35 • Jovan P Antovic NovoSeven • 12-Nov-05 Studija 2159: Sažetak efikasnosti kod pacijenata koji su preživeli prvih 48 casova U blunt traumi: rFVIIa znacajno smanjuje broj RBC, FFP i transfuzija trombocita rFVIIa znacajno smanjuje potrebe za masivnim transfuzijama (>20 jedinica RBC) Znacajano smanjenje ARDS-a (p=0.05) i rizika razvoja organske disfunkcije (MOF i/ili ARDS) (p=0.05) je takodje zapažen Moguci uticaj na broj dana proveden izvan intenzivne nege U penetrantoj traumi: Slicni trendovi, ali bez statistcke znacajnosti kod potreba za transfuzijom Trend ka redukciji potreba za masivnim transfuzijama

    36. Slide No. 36 • Jovan P Antovic NovoSeven • 12-Nov-05

    37. Slide No. 37 • Jovan P Antovic NovoSeven • 12-Nov-05 Intracerebralna hemoragija (ICH) – reci strucnjaka As you can see, there is certainly widespread recognition of the seriousness of ICH. Experts around the world recognise it to be the most dangerous type of stroke, with the highest mortality rates and the most serious consequent disabilities for those who survive. However there is still no recognised and approved treatment for ICH. As you can see, there is certainly widespread recognition of the seriousness of ICH. Experts around the world recognise it to be the most dangerous type of stroke, with the highest mortality rates and the most serious consequent disabilities for those who survive. However there is still no recognised and approved treatment for ICH.

    38. Slide No. 38 • Jovan P Antovic NovoSeven • 12-Nov-05 When comparing each active dose-group to placebo. The treatment effect is illustated here, both for ICH volume and for edema. It is evident that the total lesion is significantly larger than the hematoma in isolation. The substantial treatment effect both on the hematoma and the resulting edema may account for the dramatic clinical improvements demonstrated in the trial. Bear in mind that the brain is a closed compartment with no room for expansion and the volume of the thalamus is only about 5mL so a treatment effect of 12-15 mL is large. When comparing each active dose-group to placebo. The treatment effect is illustated here, both for ICH volume and for edema. It is evident that the total lesion is significantly larger than the hematoma in isolation. The substantial treatment effect both on the hematoma and the resulting edema may account for the dramatic clinical improvements demonstrated in the trial. Bear in mind that the brain is a closed compartment with no room for expansion and the volume of the thalamus is only about 5mL so a treatment effect of 12-15 mL is large.

    39. Slide No. 39 • Jovan P Antovic NovoSeven • 12-Nov-05 Velicina je najvažniji parametar ishoda ICH-a Pacijent sa hemoragijom velicine loptice za stoni tenis ima vece šanse ze bolji ishod nego onaj sa hemoragijom velicine loptice za golf: smrtnost kod ’stoni tenis’ velicine: apr. 40% smrtnost kod ’loptice za golf’ velicine: apr. 70%

    40. Slide No. 40 • Jovan P Antovic NovoSeven • 12-Nov-05 Smrtnost The trial showed a statistically significant reduction in mortality for the combined rFVIIa groups compared to placebo. The trial showed a statistically significant reduction in mortality for the combined rFVIIa groups compared to placebo.

    41. Slide No. 41 • Jovan P Antovic NovoSeven • 12-Nov-05 Modifikovana Rankin Skala nakon 90 dana Generalno pomeranje krive u levo 69% of placebo-treated patients died or were severely disabled (modified Rankin Scale (mRS) score 4-6), compared to 55%, 49%, and 54% of the rFVIIa-treated patients. Receiving rFVIIa more than doubled a patient’s chances of improving one level on the mRS. These results were consistent with the results shown by other standard stroke scales (Barthel Index; Extended Glasgow Coma Scale; National Institute of Health Stroke Scale; The European Quality of Life) This led to a 16% absolute reduction in the risk of death or severe disability at three months according to the mRS. 69% of placebo-treated patients died or were severely disabled (modified Rankin Scale (mRS) score 4-6), compared to 55%, 49%, and 54% of the rFVIIa-treated patients. Receiving rFVIIa more than doubled a patient’s chances of improving one level on the mRS. These results were consistent with the results shown by other standard stroke scales (Barthel Index; Extended Glasgow Coma Scale; National Institute of Health Stroke Scale; The European Quality of Life) This led to a 16% absolute reduction in the risk of death or severe disability at three months according to the mRS.

    42. Slide No. 42 • Jovan P Antovic NovoSeven • 12-Nov-05 BEZBEDONOSNI PROFIL

    43. Slide No. 43 • Jovan P Antovic NovoSeven • 12-Nov-05

    44. Slide No. 44 • Jovan P Antovic NovoSeven • 12-Nov-05 Studija 2159: Sažetak bezbednosti (svi pacijenti) Bezbedonosni problemi nisu identifikovani Nije bilo porasta MOF-a i/ili ARDS-a ni u jednoj trauma grupi tretiranoj rFVIIa Nije bilo porasta incidence: neželjenih dogadjaja tromboembolijskih fenomena

    45. Slide No. 45 • Jovan P Antovic NovoSeven • 12-Nov-05 Fatalna i arterijska tromboembolijska ozbiljna neželjena dejstva u ICH studiji There appeared to be more serious adverse event in the actively treated groups compared to placebo. However, the difference was not statistically significant (p=0.12) There appeared to be more serious adverse event in the actively treated groups compared to placebo. However, the difference was not statistically significant (p=0.12)

    46. Slide No. 46 • Jovan P Antovic NovoSeven • 12-Nov-05 NovoSeven® terapija izbora u urodjenoj hemofiliji sa inhibitorima i stecenim hemofilijama NovoSeven® aktivira koagulaciju NA MESTU OZLEDE NovoSeven® efikasna i BEZBEDNA terapija NovoSeven® je obecavajuci tretman masivnih i po život opasnih krvarenja ukljucujuci ona u traumi i ICH-u

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