New data for preventing postoperative hemorrhage with the use of aprotinin

Transcription

1 New data for preventing postoperative hemorrhage with the use of aprotinin Nikolaos BAIKOUSSIS MD, MSc, PhD Cardiac Surgeon Ippokrateio General Hospital of Athens

2 No conflict of interest

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9 Bleeding in cardiac surgery

10 ESSENTIAL ISSUES. 1 RISKS ASSOCIATED WITH: Bleeding Transfusion Re-exploration for bleeding 2 CHALLENGES ASSOCIATED WITH CABG 3 EFFICACY OVERVIEW Efficacy recap in primary and repeat CABG Efficacy in CABG patients on clopidogrel Impact of aprotinin withdrawal Aprotinin efficacy in clinical practice Unmet medical needs in clinical practice Meta-analyses 4 NAPaR REGISTRY

11 RISKS ASSOCIATED WITH BLEEDING Despite existing patient blood management methods and improved techniques and systems in cardiac surgery, excessive bleeding remains a significant problem often linked to major transfusion IN GENERAL CARDIAC SURGERY Up to 8.2% of cardiac surgery patients experience severe bleeding Up to 38% of cardiac surgery patients still require a major transfusion IN ISOLATED CABG Up to 57% of isolated CABG patients require transfusion, with a median of 3.4 units of blood transfused 23% of cardiac surgery patients require at least 4 units of blood products Severe post-operative bleeding leads to increased morbidity and mortality for cardiac surgery patients and is a relatively common complication of cardiac surgery

12 RISKS ASSOCIATED WITH TRANSFUSION Allogenic blood products transfusions can cause anaphylactic reactions or transmit infections Each RBC unit transfused is associated with a significant (29%) increase in crude risk of major infection (p<0.001) Transfusion in up to 2.4% of cardiac surgery patients can lead to transfusionrelated acute lung injury TRALI Transfusion in itself is a major risk factor for increased morbidity and mortality in isolated CABG patients Transfusions have an inherent risk, so the best outcome is to avoid the need for transfusion

13 RISKS ASSOCIATED WITH RE-EXPLORATION FOR BLEEDING Re-exploration for bleeding remains a major clinical problem Re-exploration for bleeding is a risk factor for adverse outcomes after cardiac operations In patients undergoing on-pump isolated CABG, re-operation for bleeding is required in around 2.5% of cases In isolated CABG patients on clopidogrel, re-operation for bleeding was required in 3.2% of cases Operative mortality was 4.5-fold higher in patients who required re-operation for bleeding versus those who did not: 9.1% versus 2.0% Re-operation for bleeding thus remains a significant clinical concern

14 2 CHALLENGES ASSOCIATED WITH CABG

15 CHALLENGES ASSOCIATED WITH CABG A high risk of bleeding is the major challenge associated with CABG and a number of factors are involved Increasing age increases the risk of transfusion by + 23% per decade lived Patients are older than before: the average age of patients undergoing CABG was 58 in 1991 and was 67 in 2010 Higher bleeding is associated with increasing use of antiplatelets: 3-fold increase from 21% in 2004/2005 to 79% in 2009/2010 The challenge with CABG is a stubborn high risk of bleeding

16 TRANSFUSION IS A SOCIAL AND ECONOMIC DRAIN Transfusion in itself is a significant social and economic burden Cost of supply and management is high: the mean cost of transfusing 2 units of blood is 878 in Western Europe Blood shortage is a potential problem Jehovah s witnesses refuse transfusions The need for transfusion is thus better avoided

17 1 WHAT IS APROTININ?

18 Τί είναι η απροτινίνη? Η απροτινίνη είναι ανασταλτικός παράγοντας της πρωτεάσης. Αδρανοποιεί και την ελεύθερη πλασμίνη και το σύμπλεγμα πλασμίνη- στρεπτοκινάση που σχηματίζεται ως ενδιάμεση ουσία κατά την θρομβολυτική θεραπεία με στρεπτοκινάση. Δοκιμαστική χορήγηση αρχικής δόσης 1ml ( KIU) Δόση εφόδου: προ στερνοτομής και μετά την αναισθησία KIU ενδοφλεβίως για Μετά: συνεχής έγχυση KIU ανά ώρα έως το τέλος της επέμβασης. 1 fl = ΚIU= 106 Euros

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20 CLINICAL STUDY OVERVIEW FOR APROTININ RCTs Clinical data analyses Meta-analyses Cosgrove 1992 Lemmer 1995 Levy 1995 Lemmer 1996 Van der Linden 2005 Alderman 1998 Walkden 2013 Stevens 2016 Deloge 2017 Sedrakyan 2004 Henry 2011

21 ESSENTIAL LEARNING AREAS 1 WHAT IS APROTININ? 2 HOW DOES IT ACT? 3 4 WHAT EFFECT DOES APROTININ HAVE ON HAEMOSTASIS? WHAT EFFECT DOES APROTININ HAVE ON THE PRESERVATION OF PLATELET FUNCTION? 5 WHAT ARE ITS INDICATIONS? 6 WHO IS APROTININ RESERVED FOR?

22 1 WHAT IS APROTININ?

23 WHAT IS APROTININ? Aprotinin is a non-specific serine protease inhibitor Amino-acid sequence and 3-dimensional representation of the aprotinin molecule Aprotinin is derived from bovine lung tissue Active site including lysine 15 It was first isolated in the 1930s Aprotinin is a 58-amino acid peptide The active site contains a lysine residue

24 2 HOW DOES IT ACT? How does it act? What are aprotinin s binding preferences?

25 HOW DOES IT ACT? Effects of aprotinin on serine proteases Inhibition of serine proteases: Kallikrein Plasmin Activated Protein C Thrombin Platelet bound PAR-1 Tissue Factor

26 WHAT ARE APROTININ S BINDING PREFERENCES? In-vivo inhibition of serine proteases by aprotinin Affinity of aprotinin for different protease inhibitors is dose-dependent Dosing is measured in kallikrein inhibitory units (KIU) Serine protease EC 50 plasma concentration (KIU/mL) PAR-1 receptor-thrombin Plasmin Neutrophil elastase 167 Activated protein C Plasma Kallikrein Thrombin > 1290 Tissue factor/viia complex 1430 EC 50 is the concentration required to inhibit 50% of enzyme activity

27 3 WHAT EFFECT DOES APROTININ HAVE ON HAEMOSTASIS? How does aprotinin affect haemostyasis? Aprotinin doses have different effects on haemostasis

28 HOW DOES APROTININ AFFECT HAEMOSTASIS? Effects of aprotinin on serine proteases Cardiopulmonary bypass (CPB) affects both fibrinolysis and coagulation

29 HOW DOES APROTININ AFFECT HAEMOSTASIS? Effects of aprotinin on serine proteases Blood coming into contact with the tubing of the heart-lung machine causes activation of: Plasma kallikrein Factor XII Factor XI

30 HOW DOES APROTININ AFFECT HAEMOSTASIS? Effects of aprotinin on serine proteases Trauma from surgery stimulates tissue factor, initiating the coagulation cascade

31 HOW DOES APROTININ AFFECT HAEMOSTASIS? Effects of aprotinin on serine proteases Both pathways stimulate thrombin, which activates: Platelet-bound PAR 1 Fibrinogen Protein C

32 HOW DOES APROTININ AFFECT HAEMOSTASIS? Effects of aprotinin on serine proteases Bradykinin-mediated activation of tissueplasminogen activator (TPA) stimulates plasmin Plasmin results in widespread fibrinolysis Increased activation of PAR-1 by thrombin causes yet more platelet dysfunction

33 APROTININ DOSES HAVE DIFFERENT EFFECTS ON HAEMOSTASIS Effects of aprotinin on serine proteases Aprotinin inhibits different enzymes at different doses Low-dose inhibition: Plasmin APC PAR 1 High-dose inhibition: Kallikrein Tissue factor Thrombin inhibited in dose-dependent way

34 4 WHAT EFFECT DOES APROTININ HAVE ON THE PRESERVATION OF PLATELET FUNCTION? Aprotinin also preserves platelet function

35 APROTININ ALSO PRESERVES PLATELET FUNCTION In a study in 15 patients undergoing CABG on clopidogrel showed: Aprotinin increases ADP-induced platelet aggregation from 84% to 94% (p < 0.01) A median decrease in relative platelet inhibition of > 50% Platelet aggregation after ADP stimulation (platelet count ratio,%) before and after a bolus of of 2,000,000 2,000,000 KIU of aprotinin KIU of aprotinin 15 patients in 15 with patients acute with coronary acute syndrome coronary syndrome on clopidogrel on clopidogrel undergoing primary undergoing CABG. Two primary patients CABG. have overlapping Two patients values have before overlapping (90%) values and after before aprotinin. (90%) and after aprotinin. Aprotinin makes clopidogrel-blocked ADP-receptors on platelets available to ADP stimulation

36 5 WHAT ARE ITS INDICATIONS? What is aprotinin indicated for? Who are these «High-Risk» patients?

37 WHAT IS APROTININ INDICATED FOR? Aprotinin is indicated for prophylactic CPB surgery with heart-lung machine use to reduce blood loss and blood transfusion in adult patients who are at high risk of major blood loss undergoing isolated cardiopulmonary bypass graft surgery

38 WHO ARE THESE HIGH-RISK PATIENTS? There is no consensus definition for patients at high-risk of bleeding; however, based on the ESA* recommendations, it generally include: Patients receiving dual anti-platelet therapies (e.g. clopidogrel + aspirin) or oral anticoagulants Patients undergoing repeat surgery Elderly patients Patients with uncorrected anaemia Patients with significant non-cardiac co-morbidities *ESA: European Society of Anaesthesiology Addition factors include: Patients with inherited or acquired coagulation abnormalities, a low platelet count or platelet dysfunction Patients on new oral anticoagulants (dabigatran, rivoroxiban, apixaban) Jehovah s witnesses/refusal of blood transfusion

39 6 WHO IS APROTININ RESERVED FOR? Summary

40 3 EFFICACY OVERVIEW Efficacy recap in primary and repeat CABG Efficacy in CABG patients on clopidogrel Impact of aprotinin withdrawal Aprotinin efficacy in clinical practice Unmet medical needs in clinical practice Meta-analyses

41 CLINICAL EFFICACY DEMONSTRATED IN KEY STUDIES Source Population Claims EMA clinical dossier including all RCTs published in the 1990s Primary isolated CABG Aprotinin reduces bleeding by 43% Redo CABG Aprotinin reduces bleeding by 42% Van der Linden 2005 Overall cardiac surgery CABG patients on clopidogrel Aprotinin reduces the need for transfusion by 32%, and by 13% more with tranexamic acid Aprotinin is the only agent that has been shown to reduce the need for reoperation for bleeding Even in patients on clopidogrel, aprotinin decreased postoperative bleeding by 37% This is a brief recap of the key efficacy claims for aprotinin. Based on a meta-analysis of all RCT published in the 1990s and additional clinical data, the EMA efficacy and safety dossier for aprotinin highlights that in primary isolated CABG, aprotinin reduces bleeding by 43%, and by 42% in redo CABG. In overall cardiac surgery, aprotinin reduces the need for transfusion by 32%, and by 13% more than with tranexamic acid. Moreover, aprotinin is the only agent that has been shown to reduce the need for reoperation for bleeding (1). As we will see in the following slide, even in patients on clopidogrel, aprotinin decreased postoperative bleeding by 37% (2). References: 1) Antifibrinolytics containing aprotinin, aminocaproic acid and tranexamic acid aprotinin: aprotinin. EMA/590581/2013. European Medicines Agency; ) van der Linden J, Lindvall G, Sartipy U. Aprotinin decreases postoperative bleeding and number of transfusions in patients on clopidogrel undergoing coronary artery bypass graft surgery: a double-blind, placebo-controlled, randomized clinical trial. Circulation. 2005;112(9 Suppl):I

42 WHAT ARE THE EFFECTS IN CABG PATIENTS ON CLOPIDOGREL? Van der Linden 2005 Double-blind, placebo-controlled trial in 75 patients undergoing CABG and treated with clopidogrel randomised to: full-dose aprotinin IV intraoperatively (n=37) or placebo (n=38)

43 WHAT ARE THE EFFECTS IN CABG PATIENTS ON CLOPIDOGREL? Van der Linden 2005 Mean postoperative bleeding Total bleeding reduced by 37% in aprotinin group vs placebo (1200 ml in placebo vs 760 in aprotinin group, p < 0.001) Aprotinin patients required 50% fewer blood products vs placebo (1.8 vs 4.8 p < 0.02) Aprotinin significantly reduced the need for blood transfusions (53% vs 79%, p=0.02) Mean blood transfusions Intra-operative aprotinin decreases postoperative bleeding and the number of transfusions requirements in CABG patients on clopidogrel.

44 WHAT HAS BEEN THE EFFECT OF APROTININ WITHDRAWAL? Walkden 2013 To evaluate the effect of aprotinin withdrawal on patient outcomes Single-centre study comparing two propensity-matched cohorts: a cohort who underwent surgery prior to aprotinin withdrawal (n=3,578) a cohort who underwent surgery after aprotinin withdrawal (n=3,030)

45 WHAT HAS BEEN THE EFFECT OF APROTININ WITHDRAWAL? Walkden 2013 High risk patients Withdrawal of aprotinin from clinical use was associated with: increased transfusion increased re-sternotomy greater blood loss increased morbidity The subgroup of high-risk patients had the worst outcomes, with a significant increase in 30-day mortality Kaplan-Meier failure functions showing cumulative proportion of patients dying from any cause over the first postoperative year: pre-cessation (black), post-cessation (red) in the high-risk subgroup. Dashed lines depict 95% confidence intervals. This real-world data showed that following the withdrawal of aprotinin, patients experienced significantly poorer clinical outcomes.

46 SHOWING APROTININ EFFICACY IN ISOLATED CABG IN PRACTICE Deloge 2017 Retrospective cohort study in 4 centres in France, comparing CABG surgery patient records who received: aprotinin between 2003 and 2008 (n=1267) tranexamic acid between 2007 and 2013 (n=1229) Primary outcome: total blood loss within 24 hours of the operation Secondary outcomes: Transfusion of blood products Reoperation for bleeding Renal replacement therapy Length of ICU stay In-hospital mortality

47 SHOWING APROTININ EFFICACY IN ISOLATED CABG IN PRACTICE Deloge 2017 Aprotinin significantly lowered mean 24-h blood loss after surgery: 483 vs 634 ml (p<0.0001) Fewer patients on aprotinin required intraoperative blood transfusion: 32.7% vs 46.5% (p=0.01) Aprotinin had significantly shorter adjusted ICU stay: 61 hours vs 87 hours (p<0.001) No differences in reoperations for bleeding No differences in renal replacement therapy No differences in in-hospital mortality Primary and secondary outcomes All patients, n = 2496 Aprotinin, n = 1267 Tranexamic acid, n = 1229 P Interaction Blood loss 24h (ml) (11) 634 (11) No. of patients Periopeerative transfusion 44.5% 43.7% 46.2% a No. of patients Re-exploration for bleeding 2.7% 2.5% 3.0% No. of patients Requirement for RRT 2.1% 1.8% 6.0% No. of patients In-hospital mortality 2.5% 2.4% 2.5% No. of patients In patients undergoing isolated CABG, aprotinin is more effective than tranexamic acid in reducing postoperative blood loss, and no safety concerns were identified.

48 UNMET MEDICAL NEEDS IN CURRENT PRACTICE Stevens 2016 Analysis of cardiac surgery records (3322 patients between 2012 and 2015) To explore the need for aprotinin given the widespread use of TXA Primary outcome: incidence of major transfusion (4 RBC units or more) Results: Despite the use of TXA, 23% of cardiac surgery patients still require major transfusion Clear clinical need for an effective alternative to TXA.

49 META-ANALYSES Sedrakyan 2004 Meta-analysis from 35 CABG trials (n = 3879) Aprotinin reduces transfusion requirements (relative risk 0.61) vs placebo, with a 39% risk reduction Aprotinin therapy was NOT associated with: an increase or decrease in mortality (relative risk 0.96) myocardial infarction (relative risk 0.85) renal failure (relative risk 1.01) risk Reported outcomes and blood transfusion requirements in the aprotinin and placebo group But it WAS associated with: reduced risk of stroke (relative risk 0.53) a trend toward reduced atrial fibrillation (relative risk 0.90). Concerns that aprotinin therapy is associated with increased risk is not supported by data.

50 4 NAPaR REGISTRY

51 COCHRANE REVIEW Henry 2011 Cochrane review Included data from 252 RCTs, involving over 25,000 participants, including the BART study Aprotinin reduced RBC transfusions by 34% (relative risk 0.66) Aprotinin reduced the need for re-operation due to bleeding by 54% (relative risk 0.46) Compared with no treatment, aprotinin did not increase the risk of MI, stroke, renal dysfunction or overall mortality However, there are concerns about the reporting of adverse events in small studies Compared with the lysine analogues, aprotinin had a significant increase in the risk of death and a non-significant risk of MI, all driven by the BART study data Reported outcomes and blood transfusion requirements in the aprotinin and placebo group Aprotinin appears to be slightly more effective than the lysine analogues in reducing blood loss and the receipt of blood transfusion.

52 WHAT IS THE NAPaR REGISTRY? Nordic Aprotinin Patient Registry (NAPaR) Post-authorisation safety study (PASS): safety registry to monitor aprotinin patterns of use The registry will operate for 3 years from launch, accessible via the internet (ecrf) Data includes all relevant patient and procedure data, concomitant drugs, activated clotting time, heparin and adverse events, including renal dysfunction and anaphylaxis Data flow: All patients treated with aprotinin 10,000 KIU/ml All patients to be registered in the ecrf Data entry in ecrf based on source data Data analysis and reporting to authorities by Nordic Updates will be submitted to national pharmacovigilance authorities By November 2016, 64 patients had been entered into the registry

53 SUMMARY 1 Bleeding during cardiovascular surgery has a high risk of mortality: Bleeding from cardiac surgery in general and isolated CABG in particular increases the need for allogenic blood product transfusion Transfusion is associated with increased risks Re-exploration for bleeding is associated with increased risks CABG and transfusions are also associated with inherent risks and increased societal costs Aprotinin has been shown to be safe and effective in CABG patients on clopidogrel (Van der Linden 2005) Data from clinical practice has shown that following the withdrawal of aprotinin, clinical outcomes worsened for CABG patients (Walkden 2013, Deloge 2017) Recent meta-analyses of published studies also confirmed the safety and efficacy of aprotinin The Nordic Aprotinin Patient Registry (NAPaR) is an ongoing PASS pharmacovigilance project to confirm the safety of aprotinin in clinical practice

54 SUMMARY 2 Aprotinin is a non-specific serine protease inhibitor made up of 58 amino acids. It is derived from bovine lung tissue Aprotinin preferentially inhibits kallikrein, plasmin, activated protein c, thrombin, platelet bound PAR-1 and tissue factor It preferentially inhibits plasmin at a lower concentration and kallikrein at a higher concentration Aprotinin also preserves platelet function Aprotinin is indicated for prophylactic use to reduce blood loss and blood transfusion in adult patients who are at high risk of major blood loss undergoing isolated cardiopulmonary bypass graft surgery Although there is no strict consensus as to what constitutes a high-risk patient, this group generally includes patients taking dual antiplatelet therapy, patients undergoing redo surgery, elderly patients, anaemics, patients with co-morbidities, coagulation abnormalities or platelet dysfunction, and those on new oral anticoagulants

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