More pharmaceuticals and less plasma? Severe bleeding: from basics - - PowerPoint PPT Presentation

29/11/2013 1

More pharmaceuticals and less plasma?

“Severe bleeding: from basics to practice” Brussels, Thursday 28 November

Niels Rahe-Meyer

Clinic for Anaesthesiology and Intensive Care Medicine

29/11/2013 2

Niels Rahe-Meyer 2013

Conflict of interest

Research Support / PI CSL Behring, MSD Employee No relevant COI Consultant No relevant COI Stockholder No relevant COI Speakers Bureau No relevant COI Scientific Advisory Board CSL Behring, MSD

Franziskus Hospital | Hannover Medical School

29/11/2013 3

Niels Rahe-Meyer 2013 Franziskus Hospital | Hannover Medical School

Spahn DR. et al., Crit Care 2013;17(2):R76 Kozek-Langenecker SA. et al., Eur J Anaesth 2013;30 Grading of Recommendation Assessment, Development and Evaluation (GRADE) system

1

Strong

2

Weak

A

High

C

Low

29/11/2013 4

Niels Rahe-Meyer 2013

PRBC:FFP:platelet (1:1:1) improves early mortality

N=157, patients with trauma requiring massive transfusion

Franziskus Hospital | Hannover Medical School

FFP, fresh frozen plasma; PRBC, packed red blood cell. Dente CJ. et al., J. Trauma 2009

17 36 10 20 30 40 50 Patients mortality at 24 hours (%) PRBC:FFP:platelet (n=73) Historical control (n=84) p=0.008

Use of PRBC:FFP:platelets (1:1:1) reduced 24-hour mortality in patients with trauma

29/11/2013 5

Niels Rahe-Meyer 2013

PRBC:FFP:platelet (1:1:1) does not improve 28- day mortality Prospective RCT, n=78, patients with trauma requiring

massive transfusion; control = laboratory-results-guided transfusion protocol

Franziskus Hospital | Hannover Medical School

CI, confidence interval; FFP, fresh frozen plasma; PRBC, packed red blood cell; RR, relative risk Nascimento B. et al., CMAJ 2013

32 14 10 20 30 40 50 Patients mortality at 28 days (%) PRBC:FFP:platelet (n=40) Control (n=35) RR 2.27 (95% CI 0.98 to 9.63)

No significant advantage of 1:1:1 ratio in 28-day mortality

29/11/2013 6

Niels Rahe-Meyer 2013

Fresh frozen plasma (FFP)

Franziskus Hospital | Hannover Medical School

“We recommend the initial administration of plasma (FFP) … in patients with massive bleeding” (Grade 1B)

Spahn DR. et al., Crit Care 2013

29/11/2013 7

Niels Rahe-Meyer 2013

Platelets

Prospective study, N=41, patients likely to be massively transfused

Predictive value Sensitivity (%) Specificity (%) Positive (%) Negative (%) Platelet count ≤50x109/L or fibrinogen ≤0.5 g/L 89 93 73 96

Ciavarella D. et al., Br J Haematol 1987, 67(3):365–368.

Franziskus Hospital | Hannover Medical School

Predictors of diffuse microvascular bleeding A platelet count ≤ 50x109/L or a fibrinogen level ≤0.5 g/L were the most sensitive laboratory predictors of microvascular bleeding

29/11/2013 8

Niels Rahe-Meyer 2013

Platelets

Franziskus Hospital | Hannover Medical School

“We recommend that platelets be administered to maintain a platelet count above 50x109/L” (Grade 1C) “We suggest maintenance of a platelet count above 100x109/L in patients with ongoing bleeding and/or traumatic brain injury” (Grade 2C) “We suggest an initial dose of 4–8 single platelet units or one aphaeresis pack” (Grade 2C)

Spahn DR. et al., Crit Care 2013; 17(2):R76

29/11/2013 9

Niels Rahe-Meyer 2013

Cryoprecipitate

• 1. Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013; 2. Spahn DR. et al., Crit Care 2013

Franziskus Hospital | Hannover Medical School

“We suggest that the indication for cryoprecipitate is lack of available fibrinogen concentrate for the treatment

• f bleeding and hypofibrinogenaemia”(Grade 2C)1

“We recommend treatment with fibrinogen concentrate or cryoprecipitate in the continuing management of the patient if significant bleeding is accompanied by thromboelasto- metric signs of a functional fibrinogen deficit or a plasma fibrinogen level of less than 1.5-2.0 g/L” (Grade 1C)2

29/11/2013 10

Niels Rahe-Meyer 2013 Franziskus Hospital | Hannover Medical School

DDAVP FXIII rFVIIa Tranexam Fibrinogen PCC Contents

29/11/2013 11

Niels Rahe-Meyer 2013

Desmospressin vs control for non exposure to allogeneic blood Meta-analysis,19 RCTs, N=1387, patients undergoing

surgery

Franziskus Hospital | Hannover Medical School

CI, confidence interval; DDVAP, desmopressin; RBC, red blood cell; RR, risk ratio Carless PA et al., Cochrane Database Syst Rev 2004;1:CD001884

The use of DDAVP did not reduce the risk of exposure to allogeneic RBC transfusion compared with control

RR = 0.96; 95% CI 0.87-1.06

29/11/2013 12

Niels Rahe-Meyer 2013

Desmospressin

Franziskus Hospital | Hannover Medical School

“There is no convincing evidence that desmopressin minimises perioperative bleeding or perioperative allogeneic blood transfusion in patients without a congenital bleeding disorder” (Grade 2B)1 “We do not suggest that desmopressin be used routinely in the bleeding trauma patient” (Grade 2C)2

• 1. Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013; 2. Spahn DR. et al., Crit Care 2013

29/11/2013 13

Niels Rahe-Meyer 2013

Factor XIII vs placebo for transfusion avoidance

RCT-DB, N=409, patients undergoing cardiopulmonary bypass

64,3 65,9 64,8 20 40 60 80 100 Patients avoiding blood transfusion (%) 17.5 IU/kg FXIII… 35 IU/kg FXIII… Placebo…

Karkouti KN. et al., J Thorac Cardiovasc Surg 2013;146(4):927–39

Odds ratio 0.99 95% CI 0.57–1.72

Franziskus Hospital | Hannover Medical School

Odds ratio 1.05 95% CI 0.61–1.80

Replenishment of FXIII levels after cardiopulmonary bypass had no effect on transfusion avoidance

29/11/2013 14

Niels Rahe-Meyer 2013

Factor XIII concentrate

Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013;30:270–382

Franziskus Hospital | Hannover Medical School

“In case of ongoing or diffuse bleeding and low clot strength despite adequate fibrinogen concentrations, it is likely that FXIII activity is critically reduced. In cases

• f significant FXIII deficiency (i.e. <60%), we suggest

that FXIII concentrate (30 IU/kg) can be administered” (Grade 2C)

29/11/2013 15

Niels Rahe-Meyer 2013

rFVIIa vs placebo for exposure to allogeneic blood products RCT, N=301, trauma patients

Boffard KD. et al., J Trauma 2005;59(1):8-15

Franziskus Hospital | Hannover Medical School

p=0.03 p=0.08

A significant reduction in RBC transfusion avoidance was

• bserved with rFVIIa compared with placebo

29/11/2013 16

Niels Rahe-Meyer 2013

rFVIIa

Franziskus Hospital | Hannover Medical School

We suggest that off-label administration of rFVIIa can be considered for perioperative bleeding, which cannot be stopped by conventional, surgical or interventional radiological means and/or when comprehensive coagulation therapy fails (Grade 2C)1,2

• 1. Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013; 2. Spahn DR. et al., Crit Care 2013

29/11/2013 17

Niels Rahe-Meyer 2013

Tranexamic acid vs placebo for mortality risk

RCT-DB, N=20,211, trauma patients with, or at risk of, significant bleeding

Roberts I et al., Lancet 2011;377:1096–1101

Franziskus Hospital | Hannover Medical School

5,3 4,8 7,7 6,1 2 4 6 8 10 Treatment ≤1 h from injury Treatment 1–3 h from injury Patients who died due to bleeding (%) TXA (n=3747) Placebo (n=3704)

p<0.0001

p=0.003

Early treatment with TXA reduced the risk of death due to bleeding compared with placebo

29/11/2013 18

Niels Rahe-Meyer 2013

Antifibrinolytic therapy

Franziskus Hospital | Hannover Medical School

“We recommend that TXA or -aminocaproic acid should be considered before coronary artery bypass graft surgery” (Grade 1A)1 “We recommend that TXA be administered as early as possible to the trauma patient who is bleeding or at risk

• f significant haemorrhage…” (Grade 1A)

“We suggest that protocols for the management of bleeding patients consider administration of the first dose of TXA en route to the hospital” (Grade 2C)2

• 1. Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013; 2. Spahn DR. et al., Crit Care 2013

29/11/2013 19

Niels Rahe-Meyer 2013

2 4 6 8 10 12 14 Placebo Fibrinogen

* During the 24-hour period after the start of study medication ** Unstratified Hodges-Lehmann point estimate and corresponding non-parametric 95% confidence intervals

p<0.0001**

Units of blood components

Franziskus Hospital | Hannover Medical School

Fibrinogen concentrate vs placebo for exposure to allogeneic blood products

RCT-DB, N=61, patients undergoing cardiopulmonary bypass

Rahe-Meyer N. et al., Anaesthesiology 2013;118(1):40–50

Fibrinogen reduced the need for allogeneic blood transfusion by 85%*

29/11/2013 20

Niels Rahe-Meyer 2013 Franziskus Hospital | Hannover Medical School

We recommend treatment with fibrinogen concentrate if significant bleeding is accompanied by at least suspected low fibrinogen concentrations or function” (Grade 1C)1,2 “We recommend that a plasma fibrinogen concentration <1.5 – 2.0 g/L or ROTEM/TEG signs of functional fibrinogen deficit should be triggers for fibrinogen substitution” (Grade 1C)1,2 “We recommend that fibrinogen concentrate infusion guided by point-of-care viscoelastic coagulation monitoring should be used to reduce perioperative blood loss in complex cardiovascular surgery.” (Grade 1B)1

Fibrinogen concentrate

• 1. Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013; 2. Spahn DR. et al., Crit Care 2013

29/11/2013 21

Niels Rahe-Meyer 2013

PCC and/or fibrinogen vs FFP for exposure to allogeneic blood products Retrospective analysis, N=681,

trauma patients

Franziskus Hospital | Hannover Medical School

71 9 97 44 20 40 60 80 100 RBC transfusion Platelet concentrate administration Patients exposed to allogeneic products (%) Fibrinogen and/or PCC (n=80) FFP (n=601 for RBC transfusion, n=371 for platelet concentrate transfusion)

p=0.0001

Schöchl H. et al., Crit Care 2011;15(2):R83

TEM-guided haemostatic therapy with fibrinogen concentrate and/or PCC significantly reduced allogeneic blood products exposure

p<0.0001

29/11/2013 22

Niels Rahe-Meyer 2013 Franziskus Hospital | Hannover Medical School

We suggest that PCC … can also be administered to patients not on oral anticoagulant therapy in the presence of an elevated bleeding tendency and prolonged clotting time (thromboelastic evidence). Prolonged INR/PT alone is not an indication for PCC, especially in critically ill patients (Grade 2C)1,2 Prothrombin complex concentrate (PCC)

• 1. Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013; 2. Spahn DR. et al., Crit Care 2013

29/11/2013 23

Niels Rahe-Meyer 2013

PCC vs plasma for urgent reversal of oral anticoagulation RCT, N=202, non-surgical patients with acute major

bleeding

Franziskus Hospital gem. GmbH | Medizinische Hochschule Hannover

INR, international normalised ratio; Sarode R et al. Circulation 2013;128:1234–43

Rapid INR reduction (≤1.3 at 0.5 hr after end of infusion) was observed more frequently with 4F-PCC compared with plasma, demonstrating 4F-PCC superiority

29/11/2013 24

Niels Rahe-Meyer 2013 Franziskus Hospital | Hannover Medical School

We recommend that patients on oral anti- coagulant therapy be given PCC and vitamin K before any other coagulation management steps for severe perioperative bleeding” (Grade 1B)1,2 PCC for reversal of oral anticoagulation

• 1. Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013; 2. Spahn DR. et al., Crit Care 2013

29/11/2013 25

Niels Rahe-Meyer 2013

Safety summary (1)

Franziskus Hospital | Hannover Medical School

Compound

Fresh frozen plasma

• Increased incidence of post-injury multiple organ

failure, acute respiratory distress syndrome, and infections1

• Risk of circulatory overload, ABO incompatibility,

transmission of infectious diseases, and mild allergic reactions1

• Risk of transfusion-related acute lung injury1

Platelet concentrate

• Associated with increased morbidity and

mortality2 Cryoprecipitate • Potentially increased risk of venous thromboembolism1

• Potential risks of pathogen transmission and

immune-mediated complications2

• 1. Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013; 2. Spahn DR. et al., Crit Care 2013

29/11/2013 26

Niels Rahe-Meyer 2013

Safety summary (2)

Franziskus Hospital | Hannover Medical School

Compound

Tranexamic acid

• No increased risk of thrombosis or myocardial

infarction1

• Increased rate of seizures in patients receiving a

high dose during cardiac surgery1 Desmopressin

• No increased risk of thromboembolic adverse

events (TEE)1 Fibrinogen concentrate

• Targeted fibrinogen therapy is not associated with

increased risk of TEEs2 Prothrombin complex concentrate

• Potential risk of venous and arterial TEE, and

disseminated intravascular coagulation1,2 rFVIIa

• May increase the risk of TEEs1,2

FXIII concentrate

• No safety concerns are highlighted in the

guidelines1,2

• 1. Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013; 2. Spahn DR. et al., Crit Care 2013

29/11/2013 27

Niels Rahe-Meyer 2013

Conclusion

Franziskus Hospital | Hannover Medical School

Use of TXA, fibrinogen, PCC Use of DDAVP, FXIII, rFVIIa  TXA reduced mortality (1A)  Fibrinogen (1B) and/or PCC (2C) reduced transfusion requirements  PCC effective for urgent reversal

• f anticoagulant

therapy (1B) No convincing evidence for efficacy of desmopressin No for FXIII Conflicting evidence for rFVIIa use for bleeding management Use of FFP FFP efficacy remains unproven Increased risk of mortality and developing acute lung injury Increased risk of transfusion-associ- ated circulatory

• verload

The evidence detailed here indicates that treatment of severe bleeding could favour (some) pharmaceuticals

• ver plasma