Evaluation of current and on development POCT for the

perioperative management of bleeding

Martin Besser Addenbrooke’s Hospital & Royal

Papworth Hospital Cambridge

Conflict of Interest

• Speaker fee: STAGO • Advisory board Vifor pharma, Novartis,

Cosmopharma • Research Support from Cosmopharma,

Haemosonics • Educational Grant Mitsubishi-Takeda

Ortmann Anesth Analg 2013;116:533–40

Background

• CLT is the accepted gold standard for transfusion management in the context of massive transfusion

• CLT has accepted transfusion threshold by international consensus

• CLT externally and internally validated and partaking in External quality schemes

• CLT has a turnaround time of up 45 minutes

POCT

• Point of Care tests – Identical substitute tests, e.g. POC INR, aPTT, DRIHEMATO – Viscoelastic tests (Cup and Pin)

• TEG5000 • ROTEM delta • Sonoclot • ClotPRO

– Cartridge Based viscoelastic tests (Resonance) • TEG 6S • ROTEM sigma • Haemosonic

– Whole Blood Platelet function analysers • PFA100 • Multiplate • VerifyNow, • (TEGPM)

Physiology vs available Laboratory analysis

• Dissection of pathology analysis into CLT values not along physiological boundaries

• Platelet count

• PT, aPTT and Fibrinogen only crude indicators of primary and secondary haemostasis

Putting the data to the test

• 52 urgent CABG+Valve cases, Mean 2.3 units (SD 1.3)

• Transfusion rates : RC 65%, Plt 29%, FFP15%, Cryo 6%

Consideration: 50% will have surgical bleeding A lot of transfusions are prophylactic 1 Mio $ question: if a patient was not going to bleed or did not bleed because of transfusion

Some outcomes matter more than others

Chest drain output would seem logical parameter to identify patients with extended length of stay Red cell transfusion seems stronger linked to hospital length of stay 2 things in addition are certain : Death and return to theatre

STOP

10%

4%

The 8 questions – Comparing against a Gold Standard

• Has there been an independent ‘Blind’ Comparison with a ‘Gold Standard’ of Diagnosis ?

• Pitfalls

– What is the gold standard ‘coagulopathy’? • Surgical eye

• Clot weight

• How much blood loss before it is surgical

– Independent is relative

Sackett et al. Clinical epidemiology. A basic science for clinical medicine, 1991

2- Appropriate Comparison • Has the diagnostic test been evaluated in a

patient sample that included an appropriate spectrum of Health and Disease and individuals with similar and commonly confused disorders

• Emergency patients requiring POC testing are very different

• Majority of patients undergoing heart surgery are male and 70

• Unusual patients bleed more

3 – More than the sum of its parts • Was the setting for this evaluation as well as

the filter through which the study patients passed been adequately described

• 50% of patients require no blood products

• The more you test the more you treat – beware fast and furious POC testing..

• Experienced surgeon/anaesthetist gatekeeping cannot be quantified

• Results will be skewed where high or low risk subgroups are tested in isolation

• Have the endpoints of failure been taken into account and appropriately weighted ?

4 – ‘Normal for Norfolk’ ?

• Has the term ‘normal’ been applied sensibly as it applies to this test

• Normal for the baseline population is male and 70

• Normal for the bleeding population is low BMI, female, emergency setting

• Normal is high cholesterol, anti platelets and dilutional coagulopathy

5 – Reproducibility of Result AND Interpretation

• Has the reproducibility of the test results (precision) and its interpretation (observer variation) been determined

• Potentially, often unclear

• Cartridges are expensive and all methodologies will have limited data on the specific area you are trying to test

• Relative risk of overtransfusion lower than undertransfusion

6 – In addition or instead of ?

• If the test is advocated as part of cluster or sequence of tests. Has its contribution to the overall validity of the cluster sequence been determined

• Often unclear

• E.g. NICE DG13 Guidance on viscoelastic testing 2014

• Beware of changes in pretest probability through patient selection (see 4)

7- No one is an island

• Have the tactics for carrying out this test been described sufficiently to permit exact replication

• Part of a larger medicolegal framework and medical tradition based on empiric national preferences rather than evidence

8 – More than a handful of Dollars

• Has the utility of the test been determined

• Bang for the $

• How many QALY saved

COPTIC study – assessed diagnostic accuracy of ROTEM, TEG5000 and M in 1833 patients Addition of these POC assays over the baseline clinical risk profile alone to predict bleeding added only 0.98% to the accuracy of 76.8% Cost benefit was £33 and gained life years were 1.6d with £8,000 per additional life year

Murphy et al. 2017 Res Pract Thomb Haemost 2017;1:242-51

Weber 2012 Anesthesiology. 2012 Sep;117(3):531-47 Ortmann 2015 .JTH Dec;13(12):228

Approx 1000 patients, small numbers, TEG=ROTEM, Sigma and 6s data lacking Success rate varies between operators

Bolliger Sem Thromb Hemost 2017 (43):386

Haemosonic Quantra® SEER device Sonorheometry

CLT Haemosonic Transfusion decision

PT CT (Clot Time) FFP

aPTT (if TT<25s) CT/ CTH FFP

Fibrinogen CS/ FCS (Clot Stiffness) Cryo or Fg concentrate

Platelets CS/ PCS Platelets

QuantraQPlus: 4 channels: Kaolin, K&Heparinase, CS:Tissue Factor, PCS:TF&Abciximab

Correlation to PT and aPTT

Problem : Heparin Contamination disproportionally affects the aPTT

Correlation to platelet count

PCS 13.5

Correlation to Clauss Fibrinogen

FCS2

PCS <13.5 PCS>13.5

Platelets <100 12 3 15 sens 80%

Platelets >=100 26 113 139 Spec 81%

28 PPV 0.42 116 NPV 0.97 154

CT**>159 CT**<159

aPTT>48s 9 6 15 sens 60%

aPTT<48s 5 75 139 Spec 81%

14 PPV 0.64 81 NPV 0.92 154

** Convergence of PT and aPTT onto CT leads to different cut off values

Prospective Validation

• A leap of faith

• No transfusion algorithm survives contact with the bleeding patient

60

Min

ute

s

Plt count