Presentation Transcript

1. SD plasmaProduct differences between Europe and the USClinical experience in Europe

   Bjarte G. Solheim MD, PhD, MHA Professor emeritus Institute of Immunology FDA BPAC 09.19.2012
2. European SD plasma SD treatment was adapted to plasma in a collaboration between Octapharma and Horowitz and Bonomo at the New York Blood Center * SD treated plasma was introduced in Europe by Octapharma (Octaplas) in 1991 and the US by Vitex (Plas+SD) in 1998 but production ceased there in 2002-2003 So far more than 12.5 mill bags (200 ml) of European SD plasma have been produced by Octapharma in Vienna, and licensees in Germany, France, Italy and South Africa At least 4 mill patients treated Plasma pools for SD treatment are mostly 380 litres (60 L in France) (Pool size in plasma protein production 4 000 – 30 000 litres) ** Transfusion effect is predictable because pooling results in a highly standardised content of plasma proteins including coagulation factors and inhibitors Harmful antibodies and allergic substances are diluted/neutralized A universal product is produced by pooling of (O), A, B and AB plasma (Bioplasma FDP in South Africa and Uniplas by Octapharma) * Horowitz B in The PenultimatePradigmShift, AABB Press, 2010, pp231-242 ** Hellstern P, Solheim BG Transfus Med Hemother 2011;38:65-70
3. Influenceof plasma source and delayedfreezing Runkel S et al., Transfusion 2005;45:427-32 (After P. Hellstern)
4. Protein S activitylevelsbelow 60 U/dL AP frozenwithin 4h after donation2/60 RP frozenwithin 4h after donation0/100 RP frozen 15h after donation21/60* * p<0.0001 (chi-square test) After P. Hellstern
5. European versus US SD plasma (1) Although the SD treatment is the same, the production method for the European SD plasma, Octaplas(Octapharma), differs from the method applied in the US for PLAS+SD® (Vitex) Starting material: Europe: apheresis or recovered plasma optimally frozen within 4 - 8 hrs. US: recovered plasma frozen 15 hours after collection Smaller batch size (60-380 L versus 600-1,500 L) Pool size increases the process time, which can affect labile proteins Production differences Castor oil vs. Soybean oil Sodium dihydrogenphosphate vs. calcium chloride A final ultrafiltration step performed by Vitex is omitted. Solheim, BG and Hellstern P. Transfusion 2003; 43: 1176-77 Hellstern P. CurrOpinHematol 2004;11:346-50 Salge-Bargels U et al. Transfusion Medicine 2006:16;266-77
6. European and US SD plasma (2) Both products are within normal values for most plasma proteins including FV, FVII, FVIII, FIX, C1 inhibitor, Protein C and thrombin-antithrombin complexes Plasma protein content in European SD plasma is 10-15% lower than in FFP due to dilution during the manufacturing process. This effect was omitted in the US SD plasma through a final ultrafiltration process .
7. Major differences between European and US SD plasma * n=12 ** n=8 *** n=2 Solheim BG and Hellstern P. Transfusion 2003;43:1176-77 Salge-Bartels U. Transfusion Medicine 2006;16:266-75
8. Conclusion European and US SD plasma differ in their composition The quality of the starting material determines the quality of the final SD plasma bags significantly Citrate concentrations below 10mM found in US SD plasma are suspicious of causing coagulation activation The clinical significance of reduced protein S and low plasmin inhibitor in European SD plasma is discussed in the following
9. 29 years experience with SD plasma in Norway Population 5 million 205,000 whole blood collections 15.000 apheresis procedures, (5000 plasmapheresis) SD treated plasma proteins introduced in 1988 Clinical study with Octaplas in open heart surgery 1992 SD plasma (Octaplas) substituted FFP in 1993, and so far more than 740 000 bags have been distributed
10. Consumption of plasma, FFP/SD-plasma and albumin Bags / portions per million inhabitants Start of SD plasma Year
11. Norwegian clinical trials with Octaplas In 1992, a clinical trial at Oslo University Hospital – Rikshospitalet, demonstrated that Octaplas is an adequate substitute for fresh frozen plasma (FFP) in high risk open heart surgery patients Solheim et al. The use of Octaplas in patients undergoing open heart surgery. In: Muller-Berghaus G et al (eds) DIC: Pathogenesis. Diagnosis and therapy of disseminated intravascular fibrin formation. Elsevier Science, 1993, pp 253-262 After substitution of FFP by Octaplas in Norway in 1993 a SD plasma follow up study was performed at Rikshospitalet* from May 1994 through December 1995. * Oslo University Hospital - Rikshospitalet is Regional Hospital for Health Region East & South and National Centre for cardiac surgery in children and complicated adult cases. In addition it is the National Center for allogeneic transplantation
12. Octaplas follow up study 1201 consecutive open heart surgical procedures in 1169 patients Adults: 921 Transfused 610 (66%) Transfused with Octaplas: 450 Octaplas only: 108 Children (15 years): 279 Transfused 198 (71%) Transfused with Octaplas: 122 Octaplas only: 63
13. Octaplas follow up study - safety The study showed That Octaplas is an adequate substitute for FFP in open heart surgery Only mild allergic reactions No red blood cell antibodies Viral safety was specially analysed in 343 patients with adequate pre-operative and 6-12 months follow up blood samples This analysis demonstrated no transmission of viral disease caused by: HBV, HCV, HIV, HTLV, CMV or HAV and Parvovirus B19 Solheim et al. Viral safety of solvent/detergent-treated plasma Transfusion 2000;40:84-90
14. Transfusion of Large Doses of Octaplas Children Neonates on ECMO treatment: 30% of body weight during 3-5 weeks (two patients) Adults TTP, woman 66 years, 169,4 litres during 33 months (77,8 litres in August 1996!) ECMO treatment: 30% of body weight in 6 weeks (one patient)
15. Octaplasin liver transplantation Over 800 orthotopic liver transplants – all at OUH - Rikshospitalet Only Octaplas and platelet concentrates are generally given for coagulation support Because Octaplas has a reduced concentration of the liver synthesised acute phase serine protease inhibitor antiplasmin, the serine protease inhibitor Aprotinine, was initially used in patients with severe liver failure (including liver transplants due to liver failure). This is now replaced by tranexamic acid except in some very few OLT patients requiring a broad spectrum serine protease inhibitor. Monitoring with throboelastography is often applied * The period 2005-2009 was specially analysed ** 250 consecutively transplanted patients (214 adults, 36 children) No episodes of TRALI (or other severe transfusion reactions) Episodes of fibrinolysis easily treated with tranexamicacid and not considered a clinically significant problem No major thromboembolic events Experience: Octaplas is safe and effective * Solheim BG, Flesland O in The PenultimatePradigmShift, AABB Press, 2010, pp 125-135 ** Haugaa H et al. Liver Transplantation2012;18:Suppl S1,189
16. Plasma exchange with Octaplas Over 3000 plasma exchanges with Octaplas (10 - 20 patients per year since 1993) Either centrifuge (Baxter CS-3000) or membrane technique (ASAHI membranes). Most frequent indications Guilain-Barré syndrome and myasthenia gravis Other indications TTP/HUS, and some cases of acute progressive glomerulonephritis, Goodpasture’s syndrome, systemic lupus erythematosus, Waldenström’smacroglobulinemia and Wegener’s granulomatosis. In 2010-2011: 435 plasma exchanges were performed on TTP/HUS patients, and in no instances was there observed venous thrombembolism as a complication of the plasma exchange Experience: Octaplas is safe and effective, allergic reactions are only rarely observed
17. Norwegian hemovigilance dataAdverse reactions in 2004-2011 Before 2004 two serious adverse events were reported to the pharmaceutical authorities * Rate per 100.000
18. Clinicaluse of FFP in Western Europeancountries in 2009 Unitsper 1,000 inhabitants Volume of FFP units varies from 200 to 300 ml Council of Europe data After T Krusius
19. Clinical use of Octaplas or licensees in Europe in 2008 Council of Europe data
20. Clinical experience and studies with European SD plasma 18 studies and retrospective analyses (4 prospective randomized) covering all indications for plasma document the excellent clinical efficacy and tolerance of Octaplas Although the studies lacked statistical power to detect minor differences, they clearly show that the loss of coagulation factors and inhibitors does not result in any significant loss of clinical efficacy or tolerance The studies have included different kind of patients Coagulopathy/DIC associated with surgical bleeding, cardiac surgery, obstetric complications, intrauterine transfusions, liver disease or liver transplantation Inherited coagulation disorders Plasma exchange due to TTP or immune modulation Neonates, children and adults Solheim BG, Hellstern P in The Penultimate Pradigm Shift, AABB Press, 2010, pp 69-98
21. Modified after T. Krusius
22. Plasma transfusions in France Andreu G, in The Penultimate Pradigm Shift, AABB Press, 2010, pp 137-151
23. Serious allergic reactions with plasma during 2007-2008 in France p=0.004 compared to the other plasma Andreu G, in The Penultimate Pradigm Shift, AABB Press, 2010, pp 137-151
24. Risk of fibrinolysis Because antiplasminis a liver synthesised acute phase serine protease inhibitor of plasmin, this could result in fibrinolysis in patients with severe liver failure. In 2003 de Jonge et al. reported laboratory signs of fibrinolysis during OLT when using Octaplas, but no significant differences in blood loss. After introduction of low dose Aprotinin neither venous thromboembolism (VTE) nor fibrinolysis occurred in 120 subsequent OLT treated with Octaplas No other studies or hemovigilance reports indicate VTE or fibrinolysis in OLT with European SD plasma Recently fatal fibrinolysis in 2 out 22 OLT receiving Octaplas have been reported in Ireland by Manger et al. (This Octaplas was produced from US plasma frozen 15 hours after donation) de Jonge et al. AnesthAnalg2002;94:1127-31 and 2003;96:1231–1232. Manger JJ et al. J Card VascAnest 2007; 21:410-413 Murphy WG, Mikulich O, in The Penultimate Pradigm Shift, AABB Press, 2010, pp 153-167
25. Risk of venous tromboembolism In 2003 Yarranton reported that 8 TTP patients plasma exchanged (PE) with Octaplas developed venous thromboembolism (VTE). However the same group reviewed 50 acute TTP episodes in 2007 concluding with no VTE or treatment differences between CPP and Octaplas except fewer allergic/urticarial and citrate reactions with Octaplas No other studies or hemovigilance reports indicate VTE in TTP patients PE with European SD plasma In Norway where more than 3000 PE have been performed with Octaplas we consider TTP patients to be at risk for VTE when thrombocytes normalize during PE, and therefore Routinely take precautions with LMV Heparin Elastic stockings Yarranton H et al. Br J Haematol 2003,121:778-85 Scully M et al. Vox Sang 2007;93:154-8
26. Allo- and autoantibodies in plasma FFP HLA-antibodies Complement dependant cytotoxicity 1-2% of blood products Solid-phase fluorescence technologies (308 samples) 22.5% (7.6% anti-HLA class I, 6% class II, 8.9% class I+II) Bray RA et al. Human Immunology 2004: 65; 240-244 Autoantibodies, high avidity IL-1, IL-6, IL-10, INF-a, GM-CSF, low level 3-75%, high level < 1% SD plasma HLA / granulocyte antibodies ELISA (58 FFP and 12 Octaplas batches) FFP: 9% (5 anti-HLA class I, 3 also anti-HLA class II) Octaplas: all negative Sinnot P et al. EurJournImmunogen 2004: 31; 271-274 ELISA and immunofluorescence (20 Octaplas batches) All negative for anti-HLA class I and II and anti-granulocyte Sachs U et al. Transfusion 2005:45;1628-1631 Autoantibodies Only low level (as in IVIG) Bendtzen K et al. Im Today 1998;19:209-211
27. TRALI Often initiated by a combination of underlying disease and a blood transfusion event. Important transfusion related initiators: Leukocyte-reactive antibodies Activated lipids Antibody dependent TRALI most severe and with the highest mortality Single Hospital prospective follow up 8 in 100 (Gajic et al. 2007) to 1 in 7900 (Popovsky et Moore 1985) FFP units. Mortality approximately 1 in 10 Register data 1 in 30 000 (SHOT 2003) to 1 in 66 000 (Keller –Stanislawsky et al. 2010) FFP units, mortality 1 in 4 or higher Reduction of TRALI by male only plasma 41% (Wright et al. 2008), 40% (Wiersum-Osselton et al. 2011), but almost 100% in SHOT where the definition of TRALI requires the presence of leukocyte antibodies in donor plasma No documented reports of TRALI after transfusion of more than 12.5 mill bags of SD plasma to approximately 4 mill patients Not to be discounted is a possible effect of SD treatment on activated lipids associated with TRALI
28. Pharmaco economics Cost-effectiveness of European SD plasma Because of low residual risk for recognised viral infections, cost-effectiveness of pathogen reduction is low in industrialised countries Cost of a quality adjusted life year is over US$ 7.5 mill Cost-effectiveness of SD treatment combined with elimination of TRALI and significant reduction of allergic/anaphylactic adverse events (Octaplas/OctaplasLG) Depending on the estimated frequency of TRALI the cost of a quality adjusted life year has been calculated between US$ 8315 and US$ 40 000 Jackson BR et al. JAMA 1999;282:329 vanEerd MC et al. TransfusApherSci 2010;43:251-9 Riedler GF et al. Vox Sang 2003;85:88-95
29. ConclusionExperience with European SD plasma Over 12.5 mill bags of Octaplas or licensees have been transfused to more than 4 mill patients Octaplas can be used in all indications for all patient groups including newborns TTP and liver transplant patients can be transfused safely There is no need for regular FFP or CPP Special blood cell components including exchange transfusions, can be prepared in Octaplas Incidence of anaphylactic and allergic reactions including serious adverse reactions, are significantly reduced No TRALI reactions have been documented No cases of virus disease transmission have been reported Hospital blood banks and clinicians are satisfied with the safety and clinical efficacy of the standardized product with a predictable effect