Activated Clotting Time Applications, Therapeutics and Technologies ITC Educational Services, Edison, NJ Marcia L. Zucker, Ph.D. Director of Clinical Support.

Activated Clotting TimeApplications, Therapeutics and

Technologies

ITC Educational Services, Edison, NJ

Marcia L. Zucker, Ph.D.Director of Clinical Support

Response Biomedical Corporationmzucker@responsebio.com

There was…..

• The Lee-White clotting time– Add blood to glass tube, shake

• No activator

• Manual

– Place in heat block– Examine for clot every 30 seconds

• Very slow

• Subjective clot detection

Time goes on…

1966 - Hattersley• Activated Clotting Time

– Add blood to glass tube with dirt, shake• Diatomaceous earth activator• Still manual

– Place in heat block– Visual clot detection

• Subjective clot detection

Particulate Contact Activation

• Initiation of intrinsic coagulation cascade– Factor XII (Hageman factor)– Prekallikrein (Fletcher factor)

• Shortens contact activation period

• Proposed as both screening assay for coagulation defects and for heparin monitoring

• Critical fibrin clot endpoint

Semi - Automation - 1969• HEMOCHRONOMETER

– Later - HEMOCHRON

– Add blood to tube, shake• Manual sample treatment

– Place in test well• Automated heating

• Objective fibrin clot detection

– two different activators • CA510 (later FTCA510)

– diatomaceous earth – P214 glass bead

Mechanical Detection• Magnet in tube, detector in instrument• Upon fibrin clot formation, magnet is deflected• Clotting time displayed

Two assays for separate uses

1980’s • HemoTec ACT

(later Medtronics ACTII)– Add blood to dual cartridge

• Liquid kaolin activator

– Place in instrument• Automated mixing

– Objective clot detection• Flag moves up and down• As fibrin forms, motion slows• Mechanical clot detection• Instrument displays clotting time

Lower values than CA510 –

differences ignored by clinicians

1980’s - ACT Differences• Reported in literature >20 years

– Clinical evaluations of Hemochron - mid 1970’s– By 1981 –

• poor correlation between ACT and heparin level– By 1988

• Hemochron and HemoTec clinically different

• Early ’80’s to Present– Improved clinical outcome with ACT use

• Reviewed: Draft NACB Laboratory medicine practice guideline for point of care coagulation testing

– http://www.nacb.org/lmpg/poct_LMPG_draft_PDF.stm

1990’s• Microsample ACTs - Hemochron Jr

– Add blood to sample well, press start• Silica, kaolin and phospholipid (ACT+)

• Diatomaceous earth (ACT-LR)

• Automated sample measurement

• Automated mixing

– Objective clot detection• Sample pumped across restriction

• Flow slows with clot formation

• Optics measure motion

• Clotting time displayed

Clotting Times Different

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50 100 150 200 250 300 350 400 450 500FTCA510 ACT

Jr.

AC

T

ACT+

ACT-LR

FTCA510

2000• Abbott - i-STAT

– Add blood to cartride, press start

• Diatomaceous earth or kaolin

– Insert into instrument• Automated mixing

– No clot detection• Synthetic thrombin substrate• Electro-active compound formed

and detected amperometrically• “Clotting time” reported

Clotting Times Likely Different

• i-STAT ACT Package Insert– Used to monitor moderate- and high-level heparin– Prewarmed vs. non-prewarmed calibration modes– Good correlation with Hemochron (Celite below)

• Intercept varied by site (+4 to -73 sec)

• Slope range 0.85 – 1.19

– Few publications• All show wide scatter vs Hemochron or Medtronics

Today• Hemochron Response

• Hemochron Signature Elite

• Medtronics ACT Plus

• Medtronics HMS+

• Helena Actalyke XL / Mini

• Gem PCL

• Abbott i-STAT

Activated Clotting Time

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

ACT

Why do we use an ACT?• Maintain Balance

– Bleeding Thrombosis

• Point of Care– Immediate turn around– Rapidly adjust anticoagulant dosing as needed

• Heparin – half life varies by patient– Dose required varies by patient

– Potency varies by lot

• Direct thrombin inhibitors – very short half life– Require immediate intervention

– No antidote available

NACB Guidelines• National Academy of Clinical Biochemistry

• Evidence Based Guidelines for POC Testing– http://www.nacb.org/lmpg/poct_lmpg_draft.stm

• Chapter 4 – Coagulation Testing

• Caveats:– Assume all systems equally safe / effective / precise– Correlation studies excluded– Few good outcome trials

NACB Guidelines• Is there evidence of improved clinical outcome

using ACT testing? In cardiovascular surgery?• Is there evidence for optimal target times to be used with ACT

monitoring?

– Strongly recommend ACT monitoring of heparin anticoagulation and neutralization in cardiac surgery.

– (Class A, Level I at least one randomized controlled trial, Level II–1 - small randomized controlled trials, non-randomized controlled trials).

– Insufficient evidence to recommend specific target times for use during cardiovascular surgery.

– (Class I – conflicting evidence across clinical trials).

NACB Guidelines• Is there evidence of improved clinical outcome

using ACT testing? In interventional cardiology?• Is there evidence for optimal target times to be used with ACT

monitoring?

– Strongly recommend ACT monitoring of heparin anticoagulation in interventional cardiology.

– (Class A, Level II–1 - small randomized controlled trials, non-randomized controlled trials, Level II-2 – Case controlled analytic studies from more than one center or research group).

– Recommend target times specific to ACT system • Targets differ if specific platelet inhibitors are used

concurrently with heparin.

NACB Guidelines• Target Times:

– Without intravenous platelet inhibitors:• >250 seconds using the Medtronics ACTII

• >300 seconds using the HEMOCHRON FTCA510 tube – (Class B – Level II–1 - small randomized controlled trials, non-

randomized controlled trials, Level II-2 – Case controlled analytic studies from more than one center or research group).

– With the intravenous platelet inhibitors: • abciximab or eptifibatide:

– 200-300 seconds

• tirofiban: – 250 – 300

» (Class B – Level I- at least one randomized controlled trial).

NACB Guidelines• Is there evidence of improved clinical outcome

using ACT testing? In ECMO?• Is there evidence for optimal target times to be used with ACT

monitoring?

– ExtraCorporeal Membrane Oxygenation– Strongly recommend ACT monitoring to control heparin

anticoagulation during ECMO. – (Class A – Level III – opinions of respected authorities based on

clinical experience, descriptive studies or reports of expert committees).

– Target times for ECMO based on the ACT system.– (Class B – Level III – opinions of respected authorities based on

clinical experience, descriptive studies or reports of expert committees).

NACB Guidelines• Is there evidence of improved clinical outcome

using ACT testing? In other applications (e.g. vascular surgery, intravenous heparin therapy, dialysis, neuroradiology, etc.)?

• Is there evidence for optimal target times to be used with ACT monitoring?

– There is insufficient evidence to recommend for or against ACT monitoring in applications other than cardiovascular surgery, interventional cardiology or extracorporeal oxygenation.

– (Class I).

ACT - Clinical Applications

• Essential - outcome studies show evidence– Cardiac surgery– Percutaneous coronary intervention (PCI)– ECMO / (Dialysis)

• Common – insufficient evidence for “essential”– Critical care– Interventional radiology– Electrophysiology– Vascular surgery

Different ACTs for each clinical setting

Clinical Applications

• Essential– Cardiac surgery– Percutaneous coronary intervention (PCI)– ECMO / (Dialysis)

• Common– Critical care– Interventional radiology– Electrophysiology– Vascular surgery

Monitoring - ACT• Benefits

– Industry Standard Since 1970s– Recommended as 1o method in AmSECT guidelines– ACT improves outcome in CPB, PCI

• NACB draft LMPG for POC coagulation– Easy to run

• Disadvantages– Each system yields different numbers– Most sensitive to hypothermia and hemodilution – Little or no correlation to heparin level

• especially true for pediatric patients

When to choose which ACT?• Different pharmaceutical interventions

– Antifibrinolytics– Novel anticoagulants

• Different patient populations– Especially pediatric patients

• Different monitoring preferences– Heparin Level– Need for specialty assays

• Dosing• Fibrinogen

Pharmaceutical Intervention• Amicar or Tranexamic Acid

– No effect on standard celite ACT– Continued debate on efficacy

• Multiple reports of reduction in post-operative blood loss and reduced transfusion requirements

• Aprotinin– Significant elevation of Celite ACT– Two dosing regimens – Patient size independent

• Full Hammersmith– 2 x 106 KIU loading dose; 2 x 106 KIU pump prime; 0.5 x 106

KIU/hr infusion • Half Hammersmith

– 1 x 106 KIU loading dose; 1 x 106 KIU pump prime; 0.25 x 106 KIU/hr infusion

ACT Monitoring-Aprotinin Treatment• Celite® ACT

• HEMOCHRON FTCA510; Actalyke C-ACT; i-STAT ACTCelite

– Not recommended• Still used with target times of >750 seconds

• Kaolin ACT• HEMOCHRON FTKACT; Actalyke K-ACT; i-STAT ACTKaolin;

Medtronics HR-ACT

– Unaffected by moderate doses of aprotinin• Used with target times of > 480 seconds

• Combination ACT reagents• HEMOCHRON Jr ACT+; Actalyke MAX-ACT; GEM PCL ACT

– Unaffected by ALL doses of aprotinin• Used with target times of > 400 seconds

ACT Monitoring-Aprotinin Treatment

• Jones, et al. JECT. 2004;36:51–57

Novel Pharmaceuticals• None FDA approved for cardiac surgery

• Direct thrombin inhibitors (DTIs)– Used if patient at risk for HIT

• Heparin induced thrombocytopenia

• “Heparin allergy”

– Argatroban– Refludan– Angiomax

ACT Monitoring - DTIs• Argatroban

– Synthetic analog of L-arginine• Reversible binding to thrombin

– PCI monitoring: ACT 300 – 450• Papers state standard ACT targets for CPB

• Refludan– Recombinant hirudin

• Irreversible inhibition of thrombin

– Routine monitoring with aPTT• No recent reports in CPB

• Original studies used ECT - No longer available

ACT Monitoring - DTIs• Angiomax

– Synthetic analog hirudin• Reversible binding to thrombin

– PCI monitoring: HEMOCHRON ACT-LR >300• Papers state standard ACT not appropriate for CPB

ACTTy = 28.4x + 224.9

R = 0.906

ECTy = 28.8x + 154.8

R = 0.951

Hemochron Celitey = -0.68x2 + 24.4x + 149.0

R = 0.892

ACT+y = -1.4x2 + 37.8x + 170.5

R = 0.937

Medtronics kaoliny = -0.64x2 + 25.0x + 160.4

R = 0.831

0

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0 5 10 15 20

Bivalirudin (ug/ml)

Clo

ttin

g t

ime

Adapted from Zucker, et.al., JECT 2005, in press

ACTT not yet available

Patient populations• Pediatric Patients are NOT little adults

– Reports of both shorter and longer heparin half life

• Pediatric Patients are NOT all the same– In neonates, coagulation factor levels

confound dilutional effects– Once patient exceeds 2 years of age, only

dilutional effects need to be considered• These can be very important

• Test volume is critical

Pediatric MonitoringPediatric Cardiac Surgery

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baseline post-bolus on pump rewarm post-CPB

time during bypass

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ttin

g tim

e (s

ec)

FTCA510

ACT+

• Data from clinical evaluation, on file, ITC

Monitoring - Heparin Level• Benefits

– Measures concentration, not activity– Correlates with laboratory standards

• Disadvantages– Each system yields different numbers

• apples and oranges do not compare

– Correlation to anticoagulation status is still disputed– Target for neonate, pediatric and adult patients may

differ

Monitoring - Heparin Level

• Young: <4.5 years• Shayevitz, JR and O’Kelly, SW Progress in Anesthesiology, vol. IX, chapter 16 1995

Monitoring - Heparin Level• αXa / αIIa Activity - laboratory only, impractical• Not available with microsample systems• Medtronic Hepcon HMS

– Indirect measure of protamine reversible heparin activity • Thromboplastin based

• HEMOCHRON PRT– ACT based protamine titration

• HEMOCHRON HiTT– unaffected by hemodilution, hypothermia– insensitive to aprotinin

• Thrombin Time based

• Correlates with αXa and αIIa activity

Heparin Monitoring Dilemma

ACT HeparinLevel

Which Value Determines Response?

More reasons for selecting a system

• Heparin and Protamine Dose Optimization– In vitro dosing systems

• Not available on microsample systems• Hemochron RxDx

– Heparin Response Time (HRT)

– Protamine Response Time (PRT)

– PDAO

• HMS– HDR

– HPT

Heparin Dose Optimization

• Traditional dosing regimens recommend fixed drug doses by body weight.

– Regimen does not account for patients whose response to heparin is different than the average “normal” patient.

• Patients differ in their response to heparin; may be resistant or sensitive to heparin

• Can represent 20 - 40% of patient population

• Response can vary up to 12 fold between patients

• Minimize protamine dose– Reduce time for infusion

– Avoid protamine related adverse events• hypotension

• shock

• bleeding

• platelet dysfunction

Protamine Dose Optimization

Clinical Benefits• Individualize heparin dose

• Reduce blood products needed for post-operative transfusions– i.e. red blood cells, platelets, fresh frozen plasma and

cryoprecipitateJobes DR, et al. 1995. J Thorac Cardiovasc Surg 110: 36-45

• Reduced potential for protamine reaction– Protamine reduced by average of 30%

– Zucker ML., et al. 1997. J Extra-Corp Tech. 29: 176-180.

• Reduced incidence of return to OR for bleeding

Economic Benefits (US$)GROUP N

PRE / POSTAVERAGE

COST PRENET COST

POSTAVERAGE NET

SAVINGS

1oCABG 151 / 139 $787 $493 $294

1oN / C 189 / 167 $849 $601 $247

ALLREOP

28 / 34 $2,418 $1,533 $864

1oALLCMLPX

47 / 51 $2,482 $2,133 $358

Jobes DR., et al. 1996. Cost Effective Management Of Heparin/ Protamine In CP Bypass: Analysis By Type Of Surgery. Anesthes 85:3A.

Heparin neutralization verification• Test Options

– ACT - global indicator of coagulation• PDAO /ACT – protamine titration

– HEMOCHRON Response

• Heparinase ACT – enzymatic confirmation– Medtronics ACTPlus

– Thrombin time – highly sensitive to heparin• TT/HNTT – protamine titration

– HEMOCHRON Response

– aPTT - intrinsic pathway– HEMOCHRON tube systems

– HEMOCHRON microsample systems

Clinical Applications

• Essential– Cardiac surgery– Percutaneous coronary intervention (PCI)– ECMO / (Dialysis)

• Common– Critical care– Interventional radiology– Electrophysiology– Vascular surgery

Procedures• Diagnostic

– Catheterization• locate and map vessel blockage(s)• determine need for interventional procedures

– Electrophysiology

• Interventional– Balloon angioplasty– Atherectomy (roto-rooter)– Stent placement

Diagnostic – Low dose heparin

• Catheterization and Electrophysiology– 2500 - 5000 unit bolus dose– frequently not monitored– if monitored –

• ACT » HEMOCHRON FTCA510; HEMOCHRON Jr ACT-LR;

Medtronics LR-ACT: Actalyke C-ACT; GEM PCL ACT-LR

– Targets ~ 200 seconds

• aPTT

Interventional

• Angioplasty, Atherectomy, Stent placement• HEMOCHRON FTCA510; HEMOCHRON Jr ACT-LR;

Medtronics LR-ACT or HR-ACT: Actalyke C-ACT, MAX-ACT; GEM PCL ACT-LR; i-STAT ACTCelite

– 10,000 unit bolus dose or– 2 - 2.5 mg/kg– target ACT 300 - 350 seconds

• Target must be reduced if ReoPro Used– ReoPro is one of 3 “GPIIb/IIIa” Inhibitors

• GPIIb/IIIa receptor critical in platelet aggregation

Novel Pharmaceuticals• Platelet Inhibitors

– Oral• Aspirin• Plavix

– Parenteral• ReoPro• Integrilin• Aggrastat

• Low Molecular Weight Heparins (LMWH)– None FDA approved for interventional cardiology– Lovenox– Fragmin

Platelet Structure

Courtesy of Helena Laboratories

PLAVIX

ASPIRIN

Parenteral platelet inhibitors

Intervention promotes aggregation

Picture courtesy of Reopro.com

ACT Monitoring - Platelet Inhibitors• Aspirin

– No reported effects on ACT– No anecdotal reports of effects on ACT

• Plavix– No reported effects on ACT– Anecdotal reports

• Increased bleeding at sheath pull

• ACTs don’t return to “normal” prior to sheath pull– Plateau ~ 180 – 220 seconds

ACT Monitoring - Platelet Inhibitors• ReoPro

– elevates ACTs• Study used FTCA510 and Medtronics HR-ACT

– target time = 250 sec with ReoPro• determined using FTCA510 tube

• Integrelin– No reported clinically significant effects on ACT– Slight decrease in ACT

• Study used FTCA510 and ACT-LR

• Aggrastat– No reported effects on ACT

ACT Monitoring - LMWH• Fragmin

– Reports of efficacy of ACT monitoring during PCI• Studies used FTCA510; ACT-LR; HR-ACT; LR-ACT

• Lovenox– Reports that ACT not useful for monitoring in PCI

0

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Change in APTT

Change in ACT-LR

Change in Hemonox CT

Adapted from el Rouby, et.al., J Thromb Thrombolys 2005, in pressHEMONOX not yet available

Targets can change with ACT

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50 100 150 200 250 300 350 400 450 500FTCA510 ACT

Jr. A

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FTCA510

Choose ACT by application and Intended Use:

Target Test 250 - 300 ACT-LR 300 – 350 LR or ACT+

350 – 400 ACT+ or LR

>400 ACT+

Clinical Applications

• Essential– Cardiac surgery– Percutaneous coronary intervention (PCI)– ECMO / (Dialysis)

• Common– Critical care– Interventional radiology– Electrophysiology– Vascular surgery

ECMO (Dialysis)• ACT used to monitor low dose heparin

– P214 glass activated ACT has been the “standard”

• HemoTec HR and LR also used

• Targets generally 180 - 220 seconds

– Changing ACT requires changing target• Target often 220-260 with ACT-LR

• Not all ACTs have low heparin indication

• Also indicated for low dose:– GEM PCL ACT-LR; Actalyke G-ACT

Clinical Applications

• Essential– Cardiac surgery– Percutaneous coronary intervention (PCI)– ECMO / (Dialysis)

• Common– Critical care– Interventional radiology– Electrophysiology– Vascular surgery

ACT or aPTT• Determine when to pull the femoral sheath

• HEMOCHRON FTCA510; HEMOCHRON Jr ACT-LR; Medtronics LR-ACT; Actalyke C-ACT; GEM PCL ACT-LR

– Premature sheath pull can lead to bleeding.

– Delayed removal can increase time in CCU.

– Target set at each site.• ACT targets range from 150 – 220 seconds

• aPTT targets range from 40 – 70 seconds

• Monitor heparin therapy– Target times determined by each facility

• HEMOCHRON FTCA510; HEMOCHRON Jr ACT-LR; Medtronics LR-ACT; Actalyke C-ACT; GEM PCL ACT-LR

Clinical Applications

• Essential– Cardiac surgery– Percutaneous coronary intervention (PCI)– ECMO / (Dialysis)

• Common– Critical care– Interventional radiology– Electrophysiology– Vascular surgery

Low dose heparin

• Interventional Radiology – Targets generally ~250 - 300

• Sometimes target “twice baseline”• Twice baseline can differ by ACT heparin

sensitivity

– More centers targeting “increase from baseline”• e.g. >130 second increase from baseline

Clinical Applications

• Essential– Cardiac surgery– Percutaneous coronary intervention (PCI)– ECMO / (Dialysis)

• Common– Critical care– Interventional radiology– Electrophysiology– Vascular surgery

Low dose heparin• Vascular Surgery and Electrophysiology

– Targets generally ~200 – 250• frequently no monitoring

– Change from baseline is critical factor• Is heparin having an effect?• Is patient responding “normally”?

– ~20% patients “resistant” <80 sec/unit/ml blood

– ~60% patients “normal” 80-120 sec/unit/ml blood

– ~20% patients “sensitive” >120 sec/unit/ml blood

Summary

• ACT is NOT a standardized test– Each assay yields different results

• Activator differences

• Endpoint detection differences

• Current targets developed on Hemochron– First available non-manual system– Targets must be adjusted for other systems

Summary

• While all systems correlate, they yield different results

• Targets may need to be adjusted by clinical application

• Inter-operator differences minimized with microcoagulation technology

The future of ACT?