applying evidence – blood conservation in clinical practice victor a. ferraris, m.d., ph.d....

Applying Evidence – Blood Conservation in

Clinical Practice

Victor A. Ferraris, M.D., Ph.D.University of Kentucky

Linda & Jack Gill Heart InstituteLexington, KY

Real-world guideline application

Presenter Disclosure Information

Victor A. Ferraris, M.D., Ph.D.Research grant support from

American Heart Association, Aventis, Bayer, BioMarin Pharma, Guilford, Medtronic, NHLBI, and The Medicines Company.

Lecture or consulting fees from AstraZeneca, Aventis, Bayer, Network for Advancement of Transfusion Alternatives (NATA), and The Medicines Company.


Blood Conservation Guidelines

61 recommendations regarding blood conservation.6 Class I recommendations39 Class II recommendations

20 Class IIa19 Class IIb

16 Class III recommendations

Ferraris, et al. Ann Thorac Surg, 2007. (in press)


Blood Conservation Interventions – Class I Recommendations

Identify high risk preoperatively. Blood transfusion algorithm w/ point-

of-care testing. Multimodality approach. Anti-fibrinolytic drugs (esp. for high

risk) Cell saver & cell salvage Preop platelet count and HCT for risk

prediction. Ferraris VA, et al. STS Guidelines on blood conservation. Ann Thorac Surg, 2007. In press.


Class IIa or IIb Blood Conservation Interventions

Class IIa OPCAB DDAVP for high

risk only. Stop clopidogrel

5 days before OR. Continue ASA

unless totally elective.

Class IIb BT/PFA-100 for

screening in high risk. r-FVIIa for recalcitrant

bleeding. Autologous

hemodilution. Retrograde priming.

Ferraris VA, et al. STS Guidelines on blood conservation. Ann Thorac Surg, 2007. In press.


Things That Are Not Indicated for Blood Conservation (Preliminary)

Class III indicationsUnwashed shed mediastinal blood re-

infusion.PEEP for control of bleeding.Dipyridamole for ‘platelet anesthesia’.Plasma or platelet-pheresis.Routine DDAVP.Leukocyte depletion filters during CPB.



Purpose

Apply evidence-based blood conservation interventions to real world situations.

Describe the process of guideline development.


Case #1 – Clopidogrel – “the Devil’s Drug”

Patient History80 y/o woman w/ unstable

angina & continued chest pain.Cath shows 3-v CAD w/ 60% left

main.600 mg clopidogrel loading

dose before cath. (Class I recommendation by AHA/ACC).

AODM, HTN, CRF (creat = 2.0), HCT = 34%. BSA = 1.5.


Case # 1 - Questions

1. Is this patient at high risk for bleeding?

2. Can you stop anti-platelet drugs?

3. What are the options to limit bleeding in this patient?


Transfusion Profile More than 50%

do not get transfusion.

Patients who receive > 10 units of blood are in 90th percentile

10-20% of patients consume 80% of blood products.

0 2 4 6 8 10 12 14 16 18 20 21+

Units of blood products transfused

0

500

1000

1500

2000

2500

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0%

20%

40%

60%

80%

100%

Cu

mu

lativ

e p

erc

en

t

LegendFrequencyCumulative %

4445 patients having cardiac procedures w/ CPB over 4 years.

Ferraris, Int. J. Angiology, 2006.


Transfusion & Serious Morbidity

0 thru

5

6 thru

10

11 thru

15

16 thru

20

21 thru

25

26 thru

30

31 thru

35

36 thru

40

41 thru

45>45

Donor units transfused

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Fra

cti

on

wit

h s

eri

ou

s m

orb

idit

y

0.079

0.171

0.289 0.305

0.46

0.571

0.438 0.438

0.625

0.695

Serious morbidity and mortality increase with the amount transfused.


Predictors of Postoperative Bleeding – The Big 6

1) Advanced age2) Small body size or preoperative

anemia (low RBC volume)3) Anti-platelet & anti-thrombotic

drugs.4) Prolonged operation (CPB time) –

high correlation with OR type.5) Emergency operation6) Other co-morbidities (CHF, COPD,

HTN, PVD, renal failure, etc.)Ferraris VA, et al. STS Guidelines. Ann Thorac Surg. 2005;79:1454-61.; Ferraris VA, et al. Ann Surg. 2002;235:820-7.


Two Causes of Postoperative Bleeding & Blood Transfusion

Patient-related Age Red blood cell

volume Co-morbidities

CHF Renal failure COPD

Procedure-related Prolonged

operation Emergency

operation Surgical site

bleeding (‘hole in the artery’)


Age & RBC Volume

Age / RBC volume

0

2

4

6

8

10

12

14

100

200

300

400

500

600

700

800

LegendDonor units transfusedNo. of patients in Age/RBC volume range

75 y/o, 55kg, women, with preop HCT = 35%Ferraris, Int. J. Angiology, 2006.


Case #1 – Question #1

Is this patient high risk?Risk factors

AgeAnemia (red blood cell volume)Anti-platelet drugsUrgent operationMultiple co-morbidities (CRF, HTN,

AODM,

AnswerYes!


Managing Risk Factors

Anti-platelet drugs as an exampleCommon problem – almost all

patients have anti-platelet drug on-board at OR.

Evidence is available to guide decisions.

Likely to show tangible benefit.


Does Aspirin Cause Increased Postoperative Bleeding?

21 studies reviewed the effect of aspirin on postoperative bleeding.5 of 6 RCT’s showed increased

bleeding due to aspirin (Level A evidence).

Evidence less convincing in 15 observational studies (Level B or C evidence).

Ferraris VA, et al. STS Guidelines. Ann Thorac Surg. 2005;79:1454-61.


Long-term Efficacy of ASA in Reducing Long-term Efficacy of ASA in Reducing Death or MI in Patients with Unstable Death or MI in Patients with Unstable AnginaAngina

Wallentin LC et al JACC 1991;18:1587–1593

0.00

0.05

0.10

0.15

0.20

0.25

00 33 66 99 1212MonthsMonths

Probabilityof death or MI

PlaceboPlacebo

ASA 75 mgASA 75 mg

Risk ratio after 1 year 0.52Risk ratio after 1 year 0.5295% Cl 0.37–0.72 (95% Cl 0.37–0.72 (pp=0.0001)=0.0001)


Guidelines & Aspirin – the Dilemma

Aspirin causes increased bleeding. Amount of bleeding is small (0.5

units/patient)

Aspirin important for better outcome in acute coronary syndromes Nothing more important than aspirin including

heparin, thrombolytics, 2b/3a, & PCI.

STS recommendation – stop aspirin for a few days in very low risk patients, continue in all others.

Ferraris VA, et al. STS Guidelines. Ann Thorac Surg. 2005;79:1454-61.


Adapted from Angiolillo DJ et al. Am J Cardiol. 2006;97:38-43.

Variable Response to Dual Antiplatelet Variable Response to Dual Antiplatelet Therapy in the Therapy in the Steady State PhaseSteady State Phase of of TreatmentTreatment

% Platelet Aggregation (LTA-ADP 20% Platelet Aggregation (LTA-ADP 20mol/L)mol/L)

97.597.5

92.592.5

87.587.5

82.582.5

77.577.5

72.572.5

67.567.5

62.562.5

57.557.5

52.552.5

47.547.5

42.542.5

37.537.5

32.532.5

27.527.5

22.522.5

17.517.5

12.512.5

7.57.5

2.52.5

2020

1515

1010

55

00

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Bleeding riskBleeding risk Ischemic riskIschemic risk


There Is a Problem – Aspirin & Bleeding Time

Some patients have hyper-response to aspirin.

Bleeding time back to normal in 2-3 days even in hyper-responders.

0 1 2 3 4 5 6 7 8

Days following ASA ingestion

0

2

4

6

8

10

12

14

16

Te

mp

late

ble

ed

ing

tim

e (

min

)

Ferraris VA, et al. Ann Surg. 2002;235:820-7.


Another Problem – Aspirin Resistance

Topol, 20035–10% of patients taking usual

doses of aspirin are ‘aspirin resistant’. Normal platelet aggregation to ADP &

Arachidonic acid.

Aspirin resistant patients have 2 to 3 times increased incidence of death, MI, or stroke.

Gum PA, JACC. 2003;41:961-5.


ASA-R: mean aggregation ≥70% with 10 µM ADP

& ≥20% with 0.5 mg/ml AA

Clinical Outcomes: Aspirin Responsiveness

0

20

40

00 200200 400400 600600 800800

Days after Treatment

Not Aspirin Resistant, N = 309

Aspirin Resistant, N = 17

% Death, MI, CVA% Death, MI, CVA

Log rank Log rank 22=5.05, =5.05, p=0.03p=0.03

Gum, P. JACC 2003;41:961-5


What to Expect From Guidelines

Aspirin & postoperative bleeding.Guidelines recommend stopping

aspirin in only very elective patients before operation.Class IIa recommendation.

Variability in response to aspirin is common and should be expected.

Practice variation should be reduced if guidelines are followed.

Ferraris VA et al. Ann Thorac Surg. 1998;45:71-4.;Gum PA, JACC. 2003;41:961-5.


Do Thienopyridines Cause Postoperative Bleeding?

Evidence is more compelling than for aspirin

11 studies with clopidogrel & CABG. All studies show increased bleeding

when clopidogrel given within 5 days of CABG – some with increased mortality.

AHA/ACC & STS guidelines recommend stop clopidogrel for 5 days before operation, if possible.

Ferraris VA, et al. STS Guidelines. Ann Thorac Surg. 2005;79:1454-61.; www.acc.org, Accessed Jan. 2006.


Thienopyridines (Plavix®) & Postoperative Bleeding

Study Pts. Outcome in clopidogrel-treated patients.CURE Investigators. NEJM,

2005; 345:492.910

Increased major bleeding if plavix-treated within 5 days of CABG in UA/NSTEMI patients.

van der Linden, Circulation.2005;112:I276.

37Increased bleeding & re-exploration – aprotinin used in one

group

Akowuah, ATS. 2005;80:149.

24Increased mortality, transfusion, and re-exploration in

placebo - aprotinin & EACA used in one group.

Von Heymann, CCM;2005:33:2241.

36 Increased chest tube drainage & non-heme.

Lindvall, ATS. 2005;80:922. 18 Increased transfusion (heme & non-heme), & re-exploration

Ascione, ATS. 2005;79:1210.

91 Increased mortality, transfusion and re-exploration.

Chu, ATS. 2004;78:1536. 41 Increased transfusion (heme & non-heme)

Chen, JTCVS. 2004;128:425. 45 Increased transfusion (heme & non-heme)

Gansera, Thorac Cardiovasc Surg.2003;51:185.

64Increased transfusion (heme and non-heme), & re-

exploration

Ray, BMC Cardiovasc Disord, 2003;3:3.

57 Increased re-exploration & transfusion

Yende, CCM. 2002;29:2271. 51 Increased transfusion (heme & non-heme) & re-exploration.

Hongo, JACC. 2002:40:231. 59 Increased morbidity, transfusion, & re-exploration.


Variable Response to Plavix

• Large inter-individual variability in response to clopidogrel has been observed when a 300 mg loading dose (LD) is used.

• A 600 mg LD decrease the mean platelet reactivity (PR) but does not overcome the large inter-individual variability observed.

Bonello, et al., In press EHJ 2008


VASP Index

++ADP AC

cAMP

PKA

VASPVASP VASP-VASP-PP

GP 2b/3a complexGP 2b/3a complex

Fibrinogen bindingFibrinogen binding

Inactivated PlateletsInactivated Platelets

PGE1PGI2

--

Activated platelets

P2Y12 ADP-receptor

VASP index : standardized and reproducible.

Highly specific for response to clopidogrel.

Horstrup et al. Eur J Biochem 1994;225:21-7Horstrup et al. Eur J Biochem 1994;225:21-7 Geiger et al. Arterioscler Thromb Vasc Biol. Geiger et al. Arterioscler Thromb Vasc Biol. 1999;19:2007-11.1999;19:2007-11.


Definition of Low Response to Plavix Using VASP Index

The negative predictive value of the VASP index to predict MACE after PCI was 100% using the cut-off value of 50% of PR.

Bonello L, et al. J Thromb Haemost. 2007;5:1630-6

Therefore we defined low response as a post- treatment platelet reactivity ≥ 50% using the VASP index in the present study.


Bonnello – Study Design

Non-emergent PCI : ACS and Stable angina (n=406)

Loading dose (LD) ASA 250mg Clopidogrel 600mg

VASP ≥ 50%

Randomization(n=162)

CONTROL (n=84) VASP-guided LD (n=78)

Up-to 3 additional LD of 600 mg every 24 hours until VASP < 50% before PCIMaintenance dose ASA 160 mg

Clopidogrel 75 mg

1° endpoint: MACE (CV death, MI, revascularization) at 30 days

2° endpoints: TIMI major and minor bleeding at 30 days


Efficacy of VASP Index in Guiding Plavix Therapy

MACE; n (%)Control(n=84)

VASP-guided(n=78)

Cardiovascular death 2 (2) 0

Acute and Sub-acute stent thrombosis 4 (5)† 0

Revascularization 2 (2) 0

Overall MACE 8 (10)* 0

† p =0.059

* p =0.007

MACE: CV death, MI, revascularization

Log rank p =0.007



Bleeding Complications Using the VASP Index to Guide Plavix Therapy

Bleeding, n (%) Control (n=84)

VASP-guided (n=78)

TIMI Major 1 1

TIMI Minor 3 (4) 2 (3)

All, n (%) 4 (5) 3 (4)

Using additionnal clopidogrel LD in patients with low-response and according to platelet monitoring was safe.




Can you stop clopidogrel?No good information.

Common side-effect of evidence-based review.

Identify knowledge deficits.

AnswerUnknown!Not enough evidence.


Evidence-Based Blood Conservation Strategies

Top 4 Preoperative interventions

Select high risk – “pull out all the stops” Limit anti-thrombotic & anti-platelet drug effect.

Limit blood loss during operation Anti-fibrinolytics Off-pump procedures Perfusion strategies (centrifugal pump w/ membrane)

Salvage & sequester blood (not as helpful in high-risk)

Cell saver, pump salvage, etc. Hemodilution (predonation)

Manage blood resources (process of care variables) Multimodality approach Transfusion algorithm & point-of-care testing.


What Works for Blood Conservation?

Multiple interventions are better than a few ‘favorite’ interventions.

TQM approach – ‘Measurement & Management’.

‘Outcome greater than sum of parts’ Examples

Normovolumic hemodilutionAprotinin


Normovolemic Hemodilution – Class IIb Recommendation

5 prospective studies 3 showed no benefit 2 showed benefit Not possible to do meta-analysis.

Contraindications Urgent operation Anemia Sepsis

May be beneficial when used as part of a multimodality approach.


Meta-analysis – Aprotinin & CABG

21 of 29 studies showed significant reduction in blood transfusion in aprotinin-treated.


Aprotinin Safety Issues

Safety concerns3 observational studies suggest

increased renal toxicity, possibly increased mortality, and no benefit in blood usage.

No mortality benefit despite reduced transfusion – problem of competing risks.

Bayer no longer markets aprotininOnly available for compassionate use.


Anti-fibrinolytic Drugs & Guidelines

Class I.Anti-fibrinolytic drugs

indicated to reduce blood transfusion & re-exploration in high risk patient.

Aprotinin is probably best but not readily available.



Are there interventions that can help? Multimodality blood management

program is best. 61 recommendations, not just ‘one

magic bullet’. Aprotinin is not the only blood

conservation intervention!

Answer Yes!


Case #2 – Postoperative Bleeding

Patient history 62 year-old man

Unstable angina. Drug-eluting stent 2 years ago (now on ASA

only) Started on eptifibatide (Integrelin®) in CCU Uneventful 3-v CABG 4-6 hours after stopping

eptifibitide. Four hours after operation, he is bleeding 100

to 200 cc per hour. Stat Hg is 7 mg/dL He has had 1000cc of 5% albumin and 1000cc

of crystalloid solution.


Postoperative BleedingShould you be worried?

You’d better start swimmingOr you’ll sink like a stone.

… It’ll soon shake your windows

And rattle your walls.For the times they are a-changin.

Bob Dylan


Case #2 - Questions

1. Will this patient benefit from transfusion?

2. Is there an evidence-based transfusion algorithm that guides therapy in this patient?

3. Should routine clotting & coagulation tests be ordered?


More Is Known About the Risks of Blood Transfusion Than the Benefits!

RBC Shape Change During Storage

RBC Shape Change During Storage

Day 1 Day 21 Day 35Horvav T et al Horvav T et al Transfusion Transfusion 1999 39(3):277-2811999 39(3):277-281


Bleeding After PCI Is a Risk for 1-year Mortality (5,384 patients)

Independent predictors of 1-year mortality.

Ndrepepa, 2008

Variable Hazard Ratio (95% CI)

Bleeding w/in 30 days 2.96 (1.96 -4.48)

MI w/in 30 days 2.29 (1.52 – 3.46)

Urgent revascularization w/in 30d

2.49 (1.16 - 5.35)

Age (years) 2.27 (1.78 – 2.89)

Diabetes 1.47 (1.11 – 1.96)

Multivessel CAD 2.72 (1.58 -4.67)

Elevated troponin 1.77 (1.27 -2.47)

LV ejection fraction 0.71 (0.60 – 0.85)

Creatinine 1.10 (1.06 – 1.14)


Two Evil Things About Postoperative Bleeding

Blood loss Hypovolemia Shock Worse outcome

from organ failure

Re-operation for tamponade or bleeding.

Blood transfusion Diseases

transmission Immune

modulation (TRALI)

Transfusion errors


Competing Risks

Risk of intervention (e.g. PCI, CABG) Bleeding Transfusion Reintervention MI, stroke, etc.

Risks of disease state (e.g. UA/NSTEMI) Death MI Stroke

Equation favors interventions in highest risk patients



Will this patient benefit from transfusion? Jehovah’s witness would say no. There are two bad things about blood

management Blood loss Blood transfusion

Answer Highly uncertain ‘Maybe’ (consensus)

Biggest benefit may be to increase cardiac output.


Two Reasons For Variability in Transfusion Practices

Physician & institution practices are hard to manage (control is a bad word!).

Accurate & timely information is not available (‘lab’ takes too long).

Stover, Anesthesiology. 1998;88:327.


Problems with Interventions - Consensus Guidelines for RBC Transfusion

Transfusion indicated Transfusion not indicated Uncertain benefit of transfusion

Hgb ≤ 6.0 on CPB Hgb ≥ 10 after CPB without critical end-organ ischemia.

Hgb between 8 -10g/dl in a stable patient benefit is unclear.

Hgb ≤ 8.0 in high risk (age > 65, and/or co-morbidity).

Acute blood loss (30% of blood volume).

Rapid blood loss without immediate control.

Hgb ≤ 10 g/dl in certain patients with critical end-organ ischemia.



Guidelines for Transfusion of Non-red Cell Hemostatic Factors

No evidence base!Transfuse for clinical

bleeding only.

Can be guided by accurate & timely point-of-care tests (e.g. Platelet count, PFA-100, TEG, POC PT/PTT, etc.). Ferraris VA, et al. STS Guidelines on blood

conservation. Ann Thorac Surg, 2006. In press.


Transfusion Algorithms

7 RCT’s tested transfusion algorithms w/ point-of-care testing to reduce transfusion.6 of 7 RCT’s showed reduced

transfusion or re-exploration rates. Didn’t matter what type of POC testing.Various algorithms used.



Point-of-Care Testing

Fibrinolysis & fibrinogenTEG, MCA 210, TAS system

Coagulation factorsWhole blood aPTT & PT

PlateletsBleeding time, PFA-100, TEG, RPFA

Despotis, Semin Thorac Cardiovasc Surg, 11:84-104. 1999


Transfusion Algorithms & POC Testing – An Example

Study Pts Algorithm POC tests Outcome

Avidan, 2004

210 •Transfuse PRBC for Hb ≤ 8.0.

•DDAVP for abnormal PFA-100 followed by platelets if no response to DDAVP.

•Aprotinin for abnormal TEG amplitude.

•Explore for failure to respond & continued bleeding.

•TEG•PFA-100•Hepcon

Decreased transfusion of heme & non-heme blood products.

Avidan MS, Br J Anaesth. 2004; 92:178.



Is there an evidence-based transfusion algorithm that guides therapy in this patient? Defining an algorithm is more

important than the content of the algorithm.

Answer Yes! (if everybody agrees on

algorithm)



Should routine clotting & coagulation tests be ordered?Routine tests don’t help – too

little too late

AnswerNo! (point-of-care tests are best,

combined with algorithm).


Conclusions – Take Home Messages

High risk patients benefit most. Multimodality approach is best –

especially with algorithm-driven transfusion.

Benefits of blood transfusion not as great as expected.

Inconsistent response to interventions is common (e.g. aspirin and plavix).

Guideline preparation identifies deficit in data.


STS Evidence-Based Workforce

Blood conservation writing groupWriter Organization

Victor A. Ferraris, M.D., Ph.D. (Chair)

University of Kentucky

Suellen P. Ferraris, Ph.D. University of Kentucky

Sibu P. Saha, M.D., M.B.A. University of Kentucky

Constance K. Haan, M.D. University of Florida

B. David Royston, M.D. Harefield Hospital, UK

Charles R. Bridges, M.D. (Chair, Evidence-Based Workforce)

University of Pennsylvania

Robert S.D. Higgins, M.D. Rush Presbyterian, St. Luke’s Medical Center

George J. Despotis, M.D. Washington University

Jeremiah R. Brown, Ph.D. Dartmouth Univ.


Society of Cardiovascular Anesthesia Guideline ReviewersBlood conservation reviewing group

Reviewer Organization

Bruce Spiess, M.D. (Chair) Virginia Commonwealth University

Linda Shore-Lesserson, M.D. Mount Sinai School of Medicine

Mark Stafford-Smith, M.D. Duke University

C. David Mazer, M.D. St. Michael’s Hospital, Toronto

Elliott Bennett-Guerrero, M.D. Duke University

Steven E. Hill, M.D. Duke University

Simon Body, M.B., Ch.B., M.P.H. Harvard University


Thanks

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applying evidence – blood conservation in clinical practice victor a. ferraris, m.d., ph.d....

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