As the Tube Turns

Activated Clotting Time Applications, Therapeutics and Technologies Marcia L. Zucker, Ph.D. Director of Clinical Support Response Biomedical Corporation mzucker@responsebio.com ITC Educational Services, Edison, NJ 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 700 600 Clotting Time (sec) C-ACT 500 400 300 200 100 P214 CATH PTCA 2 3 ECMO 0 Dialysis 1 0 CPB 4 5 Heparin (units/ml) 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 – 700 675 650 625 600 575 550 525 500 475 Seconds Hemochron Hemotec Pre CPB 15 min 30 min 45 min 60 min 75 min 90 min 105 min differences ignored by clinicians • Reported in literature >20 years 1980’s - ACT Differences – 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 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 Sample pumped across restriction Flow slows with clot formation Optics measure motion Clotting time displayed – Objective clot detection Clotting Times Different 550 ACT+ 450 ACT-LR FTCA510 Jr. ACT 350 250 150 50 50 100 150 200 250 300 350 400 450 500 FTCA510 ACT 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 Today • Hemochron Response • Hemochron Signature Elite • Medtronics ACT Plus • Medtronics HMS+ • Helena Actalyke XL / Mini • Gem PCL • Abbott i-STAT Activated Clotting Time Extrinsic Pathway Common Pathway CLOT 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.st m • Chapter 4 – Coagulation Testing • Caveats: – Assume all systems equally safe / effective / precise – Correlation studies excluded 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 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, nonrandomized 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 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, nonrandomized 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 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 Different ACTs for each clinical setting 700 C-ACT 600 Clotting Time (sec) K-ACT ACT+ P214 ACT-LR 500 400 300 200 100 CATH PTCA 1 2 3 CCU 0 Dialysis 0 CPB 4 5 Heparin (units/ml) Clinical Applications • Essential – Cardiac surgery – Percutaneous coronary intervention (PCI) – ECMO / (Dialysis) • Common – Critical care – Interventional radiology – Electrophysiology – Vascular surgery • Benefits Monitoring - ACT – 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; 106 KIU/hr infusion 0.25 x • Celite® ACT ACT Monitoring-Aprotinin Treatment • HEMOCHRON FTCA510; Actalyke C-ACT; i-STAT ACTCelite • Still used with target times of >750 seconds – Not recommended • 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 900 800 700 600 ECT y = 28.8x + 154.8 R = 0.951 ACTT y = 28.4x + 224.9 R = 0.906 Clotting time 500 400 300 200 100 0 0 ACT+ y = -1.4x2 + 37.8x + 170.5 R = 0.937 Hemochron Celite y = -0.68x2 + 24.4x + 149.0 R = 0.892 Medtronics kaolin y = -0.64x2 + 25.0x + 160.4 R = 0.831 Adapted from Zucker, et.al., JECT 2005, in press ACTT not yet available 20 5 10 Bivalirudin (ug/ml) 15 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 Pediatric Monitoring Pediatric Cardiac Surgery 700 600 Clotting time (sec) 500 400 300 200 100 0 FTCA510 ACT+ baseline post-bolus on pump rewarm post-CPB time during bypass • 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 Heparin Monitoring Dilemma Heparin Level ACT 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 Protamine Dose Optimization • Minimize protamine dose – Reduce time for infusion – Avoid protamine related adverse events • • • • hypotension shock bleeding platelet dysfunction Clinical Benefits • Individualize heparin dose • Reduce blood products needed for postoperative transfusions – i.e. red blood cells, platelets, fresh frozen plasma and cryoprecipitate Jobes 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 / POST AVERAGE COST PRE NET COST POST $493 $601 $1,533 $2,133 AVERAGE NET SAVINGS $294 $247 $864 $358 1oCABG 1oN / C ALL REOP 1oALL CMLPX 151 / 139 189 / 167 28 / 34 47 / 51 $787 $849 $2,418 $2,482 Jobes DR., et al. 1996. Cost Effective Management Of Heparin/ Protamine In CP Bypass: Analysis By Type Of Surgery. Anesthes 85:3A. • Test Options Heparin neutralization verification – HEMOCHRON Response – ACT - global indicator of coagulation • PDAO /ACT – protamine titration • 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 ACTLR – Targets ~ 200 seconds • aPTT Interventional • Angioplasty, Atherectomy, Stent placement • HEMOCHRON FTCA510; HEMOCHRON Jr ACTLR; Medtronics LR-ACT or HR-ACT: Actalyke CACT, 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 PLAVIX ASPIRIN Parenteral platelet inhibitors Courtesy of Helena Laboratories Intervention promotes aggregation Picture courtesy of Reopro.com • Aspirin ACT Monitoring - Platelet Inhibitors – 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 250 Clotting Time Change (secs) 200 Change in APTT 150 100 50 0 5 Change in ACT-LR Change in Hemonox CT Adapted from el Rouby, et.al., J Thromb Thrombolys 2005, in press HEMONOX not yet available 10 30 Time Post Bolus (min) 60 Targets can change with ACT 550 Choose ACT by application and Intended Use: Target 250 - 300 300 – 350 350 – 400 >400 ACT+ 450 Jr. ACT ACT-LR FTCA510 350 250 150 50 Test ACT-LR LR or ACT+ ACT+ or LR ACT+ 50 100 150 200 250 300 350 400 450 500 FTCA510 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 LRACT; 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 LRACT; 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 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?