1. Hendrik Stragier, MD The use of Fibrinogen concentrate in cardiac surgery: what’s the evidence? 1

2. Fibrinogen concentrate in cardiac surgery Fibrinogen – key element in coagulation Evaluation of the problem- Pathofysiology of coagulopathy in cardiac surgery and allogen blood transfusion Why Fibrinogen concentrate? Optimal fibrinogen concentration? Source of Fibrinogen The evidence What about the gold standard – FFP in coagulopathy Take home messages 2

3. Fibrinogen: Key element in coagulation cascade 340 kDa protein Acute Phase protein Normal plasma concentration:1,5-4 g/L Functions: Primary Hemostasis (GP IIb/IIIa) Secondary Hemostasis (fibrin network, FXIIIa) 3

4. The problem: Coagulopathy in cardiac surgery patients (1) 20% of all transfusions in setting of cardiac surgery 25% of all transfusions unnecessary Post-operative bleeding: Worse outcome 4

5. The problem: Coagulopathy in cardiac surgery patients (1I) 5

6. The problem: Coagulopathy in cardiac surgery patients (1II) Pathophysiological mechanisms: Dilutional coagulopathy Consumptive coagulopathy Direct negative effect colloïds (HES) Hyperfibrinolysis hypoperfusion: acidosis and endothelial stress (tPA) 6

7. Why Fibrinogen? -57 pt: CABG + CPB Aim: describe activity of individual coagulation factors after CABG in relation to hemodilution and postoperative bleeding Ternström L.., Radulovic V., Karlsson M., Baghaei A., Hyllner M., Bylock A., Hansson KM. et al. Plasma activity of individual coagulation factors, hemodilution and blood loss after cardiac surgery: A prospective observational study. Thrombosis Research 2010; 126: 128–133. 7 1. Fibrinogen: first coagulation factor to drop below critical levels.

8. 2u Post CBP: (corrected for hemodilution) -Reduced plasma levels of fibrinogen -Reduced activity FII, FV, FX, FXIII Note: - Acute Phase respons 24u post-CPB 8

9. 2. Post-operative fibrinogen and post-operative bleeding: Inverse correlation post-operative fibrinogen level and post-operative bleeding (r= -0.33, p=0.019) (Ternström et al.) Inverse correlation pre- and post-operative FXIII level and post-operative bleeding (r = -0.34, p= 0.009 en r= -0.41, p=0.003 respectively) (Ternström et al.) 9

10. FIBRINOGEN = 10 LIMITING FACTOR FOR POST- OPERATIVE HEMOSTASIS

11. Fibrinogen concentration: when to substitute? -Last decades: 1g/L -More recently: 1.5 – 2 g/L - POC Visco-elastic testing **Yang L.., Vuylsteke A. en Gerrard C. Postoperative fibrinogen level is associated with postoperative bleeding following cardiothoracic surgery and the effect of fibrinogen replacement therapy remains uncertain. J Thromb Haemost. 2013; 11:1519-26. 11

12. Yang et al. (2013) Yang L.., Vuylsteke A. en Gerrard C. Postoperative fibrinogen level is associated with postoperative bleeding following cardiothoracic surgery and the effect of fibrinogen replacement therapy remains uncertain. J Thromb Haemost. 2013; 11:1519-26. 12

13. Source of fibrinogen 13

14. The evidence… Specific for cardiac surgery: 4 RCT Cui et al. (2010) Karlsson et al. (2009) Tanaka et al. (2013) Rahe-Meyer et al. (2013) 2 Non-RCT comparator trials Rahe-Meyer et al. (2009) 14

15. Cui et al. (2010)  31 children – severe cyanotic (HcT ≥ 54%): congenital heart disease  Fibrinogen group: N = 17 : TEG + FIB  Control group: N= 14: traditional transfusion products, clinical experience  Outcome: Transfusion ITE, transfusion total, drainage thorax, recovery conditions Cui Y., Hei F., Long C., Feng Z., Zhao Ju., Yan F., Wang Y. et al. Perioperative monitoring of thromboelastograph on blood protection and recovery for severely cyanotic patients undergoing complex cardiac surgery. Artif Organs. 2010; 34:955-60. 15

16. Cui et al. (2010) 22.5% excluded! 16

17. Karlsson et al. (2009) 20 Patiens, elective CABG Fibrinogen: n=10; pre-operative fibrinogen infusion 2g. Control: n=10; no infusion Prim. Outcome: safety endpoint (occlusion and adverse events) Second. Outcome: Bloodloss, transfusion, hemost. Param., Hb Karlsson M., Ternström L., Hyllner M., Baghaei F., Flinck A., Skrtic S. en Jeppsson A. Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery. Thromb Haemostat 2009; 102:137- 144. 17

18. Karlsson et al. (2009) Post-operative significant higher Hb in fibrinogen group Post-operative 32% reduction bloodloss No clinical adverse events in fibrinogen group, no increase in graft occlusion 18

19. Karlsson et al. (2009) BUT: no significant difference in blood transfusion 2u and 24u post-operative: no significant difference fibrinogen concentration 19

20. Tanaka et al. (2013) RiaCT trial 20 patients, valve surgery Fibrinogen group: fixed dose 4 g fibrinogen Control group: 1 u BP Visual Bleeding Scale by senior staff member Tanaka KA., Egan K., Szlam F., Ogawa S., Roback JD., Sreeram G., Guyton RA., et al. Transfusion and hematologic variables after fibrinogen or platelet transfusion in valve replacement surgery: preliminary data of purified lyophilized fibrinogen concentrate versus conventional transfusion. Transfusion 2014; 54:109-118. 20

21. Tanaka et al. (2009) No significant difference incidence transfusion PRBC, FFP, cryoprecipitate No statistical difference in post-operative bloodloss and RBC usage 21

22. Rahe-Meyer et al. (2013) RCT, placebo controlled 61 patients, N (fibrinogen): 29, N (placebo): 32, Elective aortic surgery Fibrinogen: median dose 8 g (Fibtem, MCF 22mm) Clinical relevant bleeding (60-250g) Outcome: Primary: Allogenic blood transfusion 24u post-administration Secondary: ICU stay,hospital stay, mortality 6 months, adverse events,… 22

23. Rahe-Meyer et al. (2013) Less allogenic blood transfusion (FIB) in total (FFP + PRBC +BP) (p<0.001) and individual Total avoidance in FIB group: 45% (vs. 0%) Hospital stay and ICU stay no significant difference Underpowered to say something about mortality Rahe-Meyer N., Solomon C. en Hanke A. Effects of Fibrinogen Concentrate as First-line Therapy during Major Aortic Replacement Surgery A Randomized, Placebo-controlled Trial. Anesthesiology 2013; 118:40-50. 23

24. Non-RCT Comparator trials (I) Rahe-Meyer et al. (2009) 24

25. Rahe-Meyer et al. (2009) Transfusion algorithm based on retrospective data (n=42) Control group: n= 5 : transfusion algorithm FIB group: n= 10; first line fibrinogen concentrate No blinding, no randomization Less transfusion, less bloodloss in fibrinogen group Non-RCT Comparator trials (II) Rahe-Meyer N., Pichlmaier M., Haverich A., Solomon C., Winterhalter M., Piepenbrock S. en Tanaka KA. Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: a pilot study. Br J Anaesth 2009; 102:785-92. 25

26. Comments on the evidence: (I) Only 4 RCT’s => 132 patients, 66 patients FIB –Underpowered for clinical relevant endpoints: morbidity, mortality Heterogenity –Clinical setting (hemodilution vs CPB, colloïds vs crystalloïds  complex and multifactorial coagulopathy in cardiac surgery) –Patient series from different surgery specialisms –Definition of coagulopathy? (heterogenity in methodology. (Eg. Visual bleeding scale, 5min. Compress weight) 26

27. Endpoints –Clinical irrelevant outcomes and surrogate outcomes, what about morbidity/ mortality? (Eg. Hb, coagulation parameters)  (ICU stay, exposure allogenic transfusion products,…) Exclusion criteria –Eg. Cui et al. –Cave extrapolation cardiac surgery patients (renal and liver function impairment?) Comments on the evidence: (II) 27

28. Potential sources of bias! –Allocation bias (selection bias) –Allocation concealment (selection bias) –Attrition Bias (dropouts/withdrawals) –Reporting Bias –Performance bias –Detection bias –Other bias (funding bias, baseline imbalance) Comments on the evidence: (III) 28

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30. Financial concerns 1 g RiaStap = €419 Median dose 8g: €3352 Not reimbursed Cost-benefit balance: clinical relevant endpoints: morbidity – mortality 30

31. What about the gold standard: FFP? 31

32. Conclusions FIB has theoretical advantages over FFP Lack of evidence (only 4 RCT’s, observational and retrospective studies) Need for multi-center RCT with bigger patient populations to detect statistical differences in clinical relevant endpoints as morbidity/mortality. (not only surrogate outcomes) Cost-benefit analysis should be performed 32

33. Expected studies and ongoing studies Kwapisz 2012 Nierich 2011 Nimmo 2009 Ranucci 2011: ZEPLAST Trial 33

34. Questions? 34