more pharmaceuticals and less plasma? - belgium · franziskus hospital | hannover medical school...

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More pharmaceuticals and less plasma?

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

Niels Rahe-MeyerClinic for Anaesthesiologyand Intensive Care Medicine

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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

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Niels Rahe-Meyer 2013Franziskus 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

1Strong

2Weak

AHigh

CLow

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PRBC:FFP:platelet (1:1:1) improves early mortalityN=157, patients with trauma requiring massive transfusion


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

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36

0

10

20

30

40

50

Patie

nts

mor

talit

y at

24

hour

s (%

)

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

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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


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

32

14

0

10

20

30

40

50

Patie

nts

mor

talit

y 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

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Fresh frozen plasma (FFP)


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

Spahn DR. et al., Crit Care 2013

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

Predictive value

Sensitivity(%)

Specificity (%)

Positive (%)

Negative (%)

Platelet count ≤50x109/L orfibrinogen ≤0.5 g/L

89 93 73 96

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


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

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Platelets


“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

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Cryoprecipitate

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


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

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DDAVP FXIII rFVIIa

Tranexam Fibrinogen PCC

Contents

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

surgery


CI, confidence interval; DDVAP, desmopressin; RBC, red blood cell; RR, risk ratioCarless 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

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Desmospressin


“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 usedroutinely in the bleeding trauma patient” (Grade 2C)2


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Factor XIII vs placebo for transfusion avoidanceRCT-DB, N=409, patients undergoing cardiopulmonary bypass

64,3 65,9 64,8

0

20

40

60

80

100Pa

tient

s av

oidi

ng b

lood

tr

ansf

usio

n (%

)

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 0.9995% CI 0.57–1.72


Odds ratio 1.0595% CI 0.61–1.80

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

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Factor XIII concentrate

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


“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 of significant FXIII deficiency (i.e. <60%), we suggest that FXIII concentrate (30 IU/kg) can be administered” (Grade 2C)

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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


p=0.03

p=0.08

A significant reduction in RBC transfusion avoidance was observed with rFVIIa compared with placebo

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rFVIIa


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


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Tranexamic acid vs placebo for mortality riskRCT-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

0

2

4

6

8

10

Treatment ≤1 h from injury Treatment 1–3 h from injury

Patie

nts

who

die

d du

e to

bl

eedi

ng (%

)

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

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Antifibrinolytic therapy


“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 of 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


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0

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**

Uni

ts o

f blo

od c

ompo

nent

s


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%*

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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


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

trauma patients


71

9

97

44

0

20

40

60

80

100

RBC transfusion Platelet concentrateadministration

Patie

nts

exp

osed

to

allo

gene

ic p

rodu

cts

(%)

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

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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 (thromboelasticevidence). Prolonged INR/PT alone is not an indication for PCC, especially in critically ill patients (Grade 2C)1,2

Prothrombin complex concentrate (PCC)


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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

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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


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Safety summary (1)


CompoundFresh 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


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Safety summary (2)


CompoundTranexamicacid

• 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 complexconcentrate

• 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


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Conclusion


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 of anticoagulant therapy (1B)

No convincing evidence for efficacy of desmopressinNo for FXIIIConflicting evidence for rFVIIa use for bleeding management

Use of FFP

FFP efficacyremains unprovenIncreased risk of mortality and developing acutelung injuryIncreased risk of transfusion-associ-ated circulatory overload

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

more pharmaceuticals and less plasma? - belgium · franziskus hospital | hannover medical school...

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