5 1966 - Hattersley Activated Clotting Time Add blood to glass tube with dirt, shakeDiatomaceous earth activatorStill manualPlace in heat blockVisual clot detectionSubjective clot detection
6 Particulate Contact Activation Initiation of intrinsic coagulation cascadeFactor XII (Hageman factor)Prekallikrein (Fletcher factor)Shortens contact activation periodProposed as both screening assay for coagulation defects and for heparin monitoringCritical fibrin clot endpoint
7 Semi - Automation - 1969 HEMOCHRONOMETER Later - HEMOCHRON Add blood to tube, shakeManual sample treatmentPlace in test wellAutomated heatingObjective fibrin clot detectiontwo different activatorsCA510 (later FTCA510)diatomaceous earthP214 glass bead
8 Mechanical Detection Magnet in tube, detector in instrument Upon fibrin clot formation, magnet is deflectedClotting time displayed
10 1980’s HemoTec ACT (later Medtronics ACTII) Add blood to dual cartridgeLiquid kaolin activatorPlace in instrumentAutomated mixingObjective clot detectionFlag moves up and downAs fibrin forms, motion slowsMechanical clot detectionInstrument displays clotting time
11 Lower values than CA510 –differences ignored by clinicians
12 1980’s - ACT Differences Reported in literature >20 years Clinical evaluations of Hemochron - mid 1970’sBy 1981 –poor correlation between ACT and heparin levelBy 1988Hemochron and HemoTec clinically differentEarly ’80’s to PresentImproved clinical outcome with ACT useReviewed: Draft NACB Laboratory medicine practice guideline for point of care coagulation testing
13 1990’s Microsample ACTs - Hemochron Jr Add blood to sample well, press startSilica, kaolin and phospholipid (ACT+)Diatomaceous earth (ACT-LR)Automated sample measurementAutomated mixingObjective clot detectionSample pumped across restrictionFlow slows with clot formationOptics measure motionClotting time displayed
15 2000 Abbott - i-STAT Add blood to cartride, press start Diatomaceous earth or kaolinInsert into instrumentAutomated mixingNo clot detectionSynthetic thrombin substrateElectro-active compound formed and detected amperometrically“Clotting time” reported
16 Clotting Times Likely Different i-STAT ACT Package InsertUsed to monitor moderate- and high-level heparinPrewarmed vs. non-prewarmed calibration modesGood correlation with Hemochron (Celite below)Intercept varied by site (+4 to -73 sec)Slope range 0.85 – 1.19Few publicationsAll show wide scatter vs Hemochron or Medtronics
18 Activated Clotting Time Extrinsic PathwayIntrinsic PathwayACTCommon PathwayCLOT
19 Why do we use an ACT? Maintain Balance Point of Care Bleeding ThrombosisPoint of CareImmediate turn aroundRapidly adjust anticoagulant dosing as neededHeparin – half life varies by patientDose required varies by patientPotency varies by lotDirect thrombin inhibitors – very short half lifeRequire immediate interventionNo antidote available
20 NACB Guidelines National Academy of Clinical Biochemistry Evidence Based Guidelines for POC TestingChapter 4 – Coagulation TestingCaveats:Assume all systems equally safe / effective / preciseCorrelation studies excludedFew good outcome trials
21 NACB GuidelinesIs 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).
22 NACB GuidelinesIs 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 systemTargets differ if specific platelet inhibitors are used concurrently with heparin.
23 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:secondstirofiban:250 – 300(Class B – Level I- at least one randomized controlled trial).
24 NACB GuidelinesIs 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 OxygenationStrongly 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).
25 NACB GuidelinesIs 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).
26 ACT - Clinical Applications Essential - outcome studies show evidenceCardiac surgeryPercutaneous coronary intervention (PCI)ECMO / (Dialysis)Common – insufficient evidence for “essential”Critical careInterventional radiologyElectrophysiologyVascular surgery
29 Monitoring - ACT Benefits Disadvantages Industry Standard Since 1970s Recommended as 1o method in AmSECT guidelinesACT improves outcome in CPB, PCINACB draft LMPG for POC coagulationEasy to runDisadvantagesEach system yields different numbersMost sensitive to hypothermia and hemodilutionLittle or no correlation to heparin levelespecially true for pediatric patients
30 When to choose which ACT? Different pharmaceutical interventionsAntifibrinolyticsNovel anticoagulantsDifferent patient populationsEspecially pediatric patientsDifferent monitoring preferencesHeparin LevelNeed for specialty assaysDosingFibrinogen
31 Pharmaceutical Intervention Amicar or Tranexamic AcidNo effect on standard celite ACTContinued debate on efficacyMultiple reports of reduction in post-operative blood loss and reduced transfusion requirementsAprotininSignificant elevation of Celite ACTTwo dosing regimens – Patient size independentFull Hammersmith2 x 106 KIU loading dose; 2 x 106 KIU pump prime; 0.5 x 106 KIU/hr infusionHalf Hammersmith1 x 106 KIU loading dose; 1 x 106 KIU pump prime; x 106 KIU/hr infusion
32 ACT Monitoring-Aprotinin Treatment Celite® ACTHEMOCHRON FTCA510; Actalyke C-ACT; i-STAT ACTCeliteNot recommendedStill used with target times of >750 secondsKaolin ACTHEMOCHRON FTKACT; Actalyke K-ACT; i-STAT ACTKaolin; Medtronics HR-ACTUnaffected by moderate doses of aprotininUsed with target times of > 480 secondsCombination ACT reagentsHEMOCHRON Jr ACT+; Actalyke MAX-ACT; GEM PCL ACTUnaffected by ALL doses of aprotininUsed with target times of > 400 seconds
33 ACT Monitoring-Aprotinin Treatment Jones, et al. JECT. 2004;36:51–57
34 Novel Pharmaceuticals None FDA approved for cardiac surgeryDirect thrombin inhibitors (DTIs)Used if patient at risk for HITHeparin induced thrombocytopenia“Heparin allergy”ArgatrobanRefludanAngiomax
35 ACT Monitoring - DTIs Argatroban Refludan Synthetic analog of L-arginineReversible binding to thrombinPCI monitoring: ACT 300 – 450Papers state standard ACT targets for CPBRefludanRecombinant hirudinIrreversible inhibition of thrombinRoutine monitoring with aPTTNo recent reports in CPBOriginal studies used ECT - No longer available
36 ACT Monitoring - DTIs Angiomax Synthetic analog hirudin Reversible binding to thrombinPCI monitoring: HEMOCHRON ACT-LR >300Papers state standard ACT not appropriate for CPBAdapted from Zucker, et.al., JECT 2005, in pressACTT not yet available
37 Patient populations Pediatric Patients are NOT little adults Reports of both shorter and longer heparin half lifePediatric Patients are NOT all the sameIn neonates, coagulation factor levels confound dilutional effectsOnce patient exceeds 2 years of age, only dilutional effects need to be consideredThese can be very importantTest volume is critical
38 Pediatric MonitoringData from clinical evaluation, on file, ITC
39 Monitoring - Heparin Level BenefitsMeasures concentration, not activityCorrelates with laboratory standardsDisadvantagesEach system yields different numbersapples and oranges do not compareCorrelation to anticoagulation status is still disputedTarget for neonate, pediatric and adult patients may differ
40 Monitoring - Heparin Level Young: <4.5 yearsShayevitz, JR and O’Kelly, SW Progress in Anesthesiology, vol. IX, chapter
41 Monitoring - Heparin Level αXa / αIIa Activity - laboratory only, impracticalNot available with microsample systemsMedtronic Hepcon HMSIndirect measure of protamine reversible heparin activityThromboplastin basedHEMOCHRON PRTACT based protamine titrationHEMOCHRON HiTTunaffected by hemodilution, hypothermiainsensitive to aprotininThrombin Time basedCorrelates with αXa and αIIa activity
42 Heparin Monitoring Dilemma LevelACTWhich Value Determines Response?
43 More reasons for selecting a system Heparin and Protamine Dose OptimizationIn vitro dosing systemsNot available on microsample systemsHemochron RxDxHeparin Response Time (HRT)Protamine Response Time (PRT)PDAOHMSHDRHPT
44 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 heparinCan represent % of patient populationResponse can vary up to 12 fold between patients
45 Protamine Dose Optimization Minimize protamine doseReduce time for infusionAvoid protamine related adverse eventshypotensionshockbleedingplatelet dysfunction
46 Clinical Benefits Individualize heparin dose Reduce blood products needed for post-operative transfusionsi.e. red blood cells, platelets, fresh frozen plasma and cryoprecipitateJobes DR, et al J Thorac Cardiovasc Surg 110: 36-45Reduced potential for protamine reactionProtamine reduced by average of 30%Zucker ML., et al J Extra-Corp Tech. 29:Reduced incidence of return to OR for bleeding
47 Economic Benefits (US$) Jobes DR., et al Cost Effective Management Of Heparin/ Protamine In CP Bypass: Analysis By Type Of Surgery. Anesthes 85:3A.
48 Heparin neutralization verification Test OptionsACT - global indicator of coagulationPDAO /ACT – protamine titrationHEMOCHRON ResponseHeparinase ACT – enzymatic confirmationMedtronics ACTPlusThrombin time – highly sensitive to heparinTT/HNTT – protamine titrationaPTT - intrinsic pathwayHEMOCHRON tube systemsHEMOCHRON microsample systems
50 Procedures Diagnostic Interventional Catheterization Electrophysiology locate and map vessel blockage(s)determine need for interventional proceduresElectrophysiologyInterventionalBalloon angioplastyAtherectomy (roto-rooter)Stent placement
51 Diagnostic – Low dose heparin Catheterization and Electrophysiologyunit bolus dosefrequently not monitoredif monitored –ACTHEMOCHRON FTCA510; HEMOCHRON Jr ACT-LR; Medtronics LR-ACT: Actalyke C-ACT; GEM PCL ACT-LRTargets ~ 200 secondsaPTT
52 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 ACTCelite10,000 unit bolus dose ormg/kgtarget ACT secondsTarget must be reduced if ReoPro UsedReoPro is one of 3 “GPIIb/IIIa” InhibitorsGPIIb/IIIa receptor critical in platelet aggregation
53 Novel Pharmaceuticals Platelet InhibitorsOralAspirinPlavixParenteralReoProIntegrilinAggrastatLow Molecular Weight Heparins (LMWH)None FDA approved for interventional cardiologyLovenoxFragmin
54 Platelet Structure PLAVIX ASPIRIN Parenteral platelet inhibitors Courtesy of Helena Laboratories
55 Intervention promotes aggregation Picture courtesy of Reopro.com
56 ACT Monitoring - Platelet Inhibitors AspirinNo reported effects on ACTNo anecdotal reports of effects on ACTPlavixAnecdotal reportsIncreased bleeding at sheath pullACTs don’t return to “normal” prior to sheath pullPlateau ~ 180 – 220 seconds
57 ACT Monitoring - Platelet Inhibitors ReoProelevates ACTsStudy used FTCA510 and Medtronics HR-ACTtarget time = 250 sec with ReoProdetermined using FTCA510 tubeIntegrelinNo reported clinically significant effects on ACTSlight decrease in ACTStudy used FTCA510 and ACT-LRAggrastatNo reported effects on ACT
58 ACT Monitoring - LMWH Fragmin Lovenox Reports of efficacy of ACT monitoring during PCIStudies used FTCA510; ACT-LR; HR-ACT; LR-ACTLovenoxReports that ACT not useful for monitoring in PCIAdapted from el Rouby, et.al., J Thromb Thrombolys 2005, in pressHEMONOX not yet available
59 Targets can change with ACT Choose ACT by application and Intended Use:
61 ECMO (Dialysis) ACT used to monitor low dose heparin P214 glass activated ACT has been the “standard”HemoTec HR and LR also usedTargets generally secondsChanging ACT requires changing targetTarget often with ACT-LRNot all ACTs have low heparin indicationAlso indicated for low dose:GEM PCL ACT-LR; Actalyke G-ACT
63 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-LRPremature sheath pull can lead to bleeding.Delayed removal can increase time in CCU.Target set at each site.ACT targets range from 150 – 220 secondsaPTT targets range from 40 – 70 secondsMonitor heparin therapyTarget times determined by each facility
65 Low dose heparin Interventional Radiology Targets generally ~250 - 300 Sometimes target “twice baseline”Twice baseline can differ by ACT heparin sensitivityMore centers targeting “increase from baseline”e.g. >130 second increase from baseline
67 Low dose heparin Vascular Surgery and Electrophysiology Targets generally ~200 – 250frequently no monitoringChange from baseline is critical factorIs heparin having an effect?Is patient responding “normally”?~20% patients “resistant” <80 sec/unit/ml blood~60% patients “normal” sec/unit/ml blood~20% patients “sensitive” >120 sec/unit/ml blood
68 Summary ACT is NOT a standardized test Each assay yields different resultsActivator differencesEndpoint detection differencesCurrent targets developed on HemochronFirst available non-manual systemTargets must be adjusted for other systems
69 Summary While all systems correlate, they yield different results Targets may need to be adjusted by clinical applicationInter-operator differences minimized with microcoagulation technology