Monitoring of heparin anticoagulants 7/6/ ANNUAL MEETING CONTROVERSIES AND UNANSWERED QUESTIONS IN ANTICOAGULANT THERAPY

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1 COAGULATION ASSAYS CONTROVERSIES AND UNANSWERED QUESTIONS IN ANTICOAGULANT THERAPY Kyle Davis, PharmD, BCPS APTT assay Time and cost efficient Measures time from activation to formation of stable clot Not standardized; Poor correlation Results may become confounded Monagle P (ed.), Haemostasis: Methods and Protocols, Methods in Molecular Biology, vol. 992 Anti-Xa assay Expensive, chromogenic assay Measures heparin and low molecular weight heparin levels Requires creation of standard curves Used to validate APTT Therapeutic range IU/mL OBJECTIVES CHROMOGENIC ANTI-XA ASSAY Discuss monitoring methods for heparin anticoagulants Describe techniques for monitoring direct acting oral anticoagulants Excessive amount of factor Xa added Explore VTE prophylactic and treatment strategies in obese patient populations Evaluate alternative treatment strategies in the management of heparin-induced thrombocytopenia Journal of Arrhythmia 32(2016) APTT VS ANTI-XA HEPARIN RESISTANT PATIENTS Monitoring of heparin anticoagulants Levine et al 1 Randomized patients receiving 35,000 units / 24 hours Anti-Xa patients received 4,000 less units No difference in VTE or bleeding Price et al 2 Retrospective analysis of paired APTT and anti-xa values 42% of patients with high APTT values Higher bleeding and mortality rates in consecutively discordant patients 1. Arch Intern Med. 1994;154: Ann Pharmacother 2013;47:

2 APTT VS ANTI-XA Single center observational Heparin 80units/kg followed by 18units/kg/hr Outcome APTT Anti-Xa (n=50) (n=50) p value Time to therapeutic anticoagulation (hr.) < Tests in therapeutic range (%) < Tests performed per 24 hours <0.01 Infusion rate changes per 24 hours < Major hemorrhage (%) Large RCTs evaluating the use of APTT and anti-xa assays are lacking Therapeutic anticoagulation may be achieved more rapidly with fewer complications using the anti-xa assay The anti-xa assay reduces the testing burden and is cost neutral Ann Pharmacother 2011;45: COST EFFECTIVENESS OF ANTI-XA Outcome Anti-Xa n=137 APTT n=131 p value Therapeutic anti-xa (%) Therapeutic APTT (%) Monitoring tests/24 hours < Dosage changes/24 hours < Monitoring with anti-a costs $4.96 more than APTT over 96 hours Monitoring of direct acting oral anticoagulants Pharmacotherapy 1999;19(6): LOW MOLECULAR WEIGHT HEPARIN Routine monitoring with anti-xa not recommended Interpretation of peak and trough levels not well established Standardized dose titrations currently unavailable Reserved for limited patient populations Renal impairment Pregnancy Trauma Obesity DIRECT ACTING ORAL ANTICOAGULANTS DOACs exhibit predictable PK/PD properties Routine monitoring not required Monitoring may be required Hemorrhagic complications Compliance Procedures Special populations J Thromb Thrombolysis (2016) 41: Hematology Am Soc Hematol Educ Program. 2015;2015:

3 DIRECT ACTING ORAL ANTICOAGULANTS FACTOR XA INHIBITORS Chromogenic Anti-Xa Drug Dose Trough Concentration (ng/ml) Peak Concentration (ng/ml) Same method as with other anticoagulants (heparin, LMWH) Excessive amount of Xa added Dabigatran 150mg PO BID Rivaroxaban 20mg PO Daily Apixaban 5mg PO BID Currently no FDA approved calibration materials available Use of traditional anti-xa testing may provide benefit Hematology Am Soc Hematol Educ Program. 2015;2015: Journal of Arrhythmia 32(2016) FACTOR XA INHIBITORS Prothrombin Time (PT) FACTOR XA INHIBITORS Chromogenic Anti-Xa Reagent Triniclot Excel S Neoplastin R Thromborel S Clin Appl Thromb Hemost Mar 16 (Ahead of print) Clin Appl Thromb Hemost Feb 2 FACTOR XA INHIBITORS Activated Partial Thromboplastin Time (APTT) DIRECT THROMBIN INHIBITORS APTT Pathology (January 2016) 48(1), pp Journal of Arrhythmia 31(2015)

4 DIRECT THROMBIN INHIBITORS PT-INR The most accurate and precise monitoring parameters are not widely available Routinely used assays may be of benefit in limited patient populations Thrombin time is the most sensitive assay for detecting the presence of dabigatran Factor Xa inhibitors are best monitored using chromogenic assays Eur J Clin Pharmacol (2013) 69: DIRECT THROMBIN INHIBITORS Thrombin Time (TT) Treatment and prevention of VTE in obesity Thromb Haemost 2013; 110: Agent and Assay Sensitivity Utility Dabigatran Thrombin Time Very sensitive; rapidly reaches Detects presence of drug; not maximum values quantitative aptt More sensitive than PT/INR Widely available; not quantitative PT/INR Factor Xa Inhibitors Chromogenic anti-xa PT/INR Insensitive High sensitivity and accuracy Sensitive at high concentration Not ideal; elevated level may suggest presence of drug Best available; can be used with heparin calibration Useful to detect excessive levels; best with rivaroxaban and edoxaban APTT Low sensitivity Limited by poor sensitivity Am J Health-Syst Pharm. 2016; 73(suppl 2):S14-26 UNFRACTIONATED HEPARIN Over 50% of the world will be obese by 2030 Weight is the single best predictor of heparin requirements The Raschke nomogram used actual body weight Adipose tissue is not highly vascularized J Thromb Thrombolysis (2016) 41: Actual body weight Supratherapeutic Hemorrhagic events Dosing weight Delayed anticoagulation Recurrent thrombosis 4

5 UNFRACTIONATED HEPARIN INITIAL INFUSION RATES Study Patients Outcome Comments Yee 1 ABW superior to DW and IBW; Reduction in initial rate DW vs. ABW vs patients >100kg required smaller (15IU/kg/hr) with dose (n=213) IBW doses capping Barletta 2 (n=101) Riney 3 (n=273) BMI > 40kg/m 2 BMI < 40kg/m 2 BMI > 40kg/m 2 BMI kg/m 2 BMI <25kg/m 2 Greater APTT in morbidly obese at 6 and 12 hours (155 vs 135 p=0.020; 141 vs 117 p=0.012) Morbidly obese required lower rates to achieve therapeutic APTT (11.5 vs 12.5 vs 13.5 IU/kg/hr) Dose capping may be beneficial in morbidly obese BMI should be considered when dosing LOW MOLECULAR WEIGHT HEPARIN Clinical trials utilize actual body weight to calculate dosing Concern exists over anticoagulation in obese patients Dosing capping has been recommended Studies demonstrate minimal accumulation in patients weighing 190kg with dalteparin and 159kg with enoxaparin DW: dosing weight ABW: adjusted body weight IBW: ideal body weight J Thromb Thrombolysis (2016) 41: American Journal of Health System Pharmacy, 55, Surg Obes Relat Dis 2008;4: Ann Pharmacother 2010;44: UNFRACTIONATED HEPARIN DOSE CAPPING LOW MOLECULAR WEIGHT HEPARIN DALTEPARIN DOSE RESPONSE Evaluated patients >110kg vs non-obese controls with ACS Dose of 60units/kg x 1 followed by 12units/kg/hr Bolus dose cap: 4,000 units; initial infusion cap 1,000 units/hr Patients Obese (n=30) Non-obese (n=90) p-value Time to therapeutic APTT (hr) < Number of dose adjustments < Mean day 3 anti-xa trough (IU/mL) Mean day 5 anti-xa trough (IU/mL) Mean day 3 anti-xa peak (IU/mL) ABW within 20% > IBW ABW 20-40% >IBW ABW >40% IBW P value > > >0.2 Obesity (2013) 21, Haemostasis 2001;31:42 48 REITE Registry of patients with acute, symptomatic VTE (n=8,845) Evaluated outcomes in 3 weight groups at 15 days <50kg (n=169) kg (n=8,382) >100kg (n=294) No difference in recurrent VTE, fatal PE, or hemorrhagic events UNFRACTIONATED HEPARIN In most patients heparin should be dosed on actual body weight Consider adjusted body weight in patients with a BMI >40kg/m 2 LOW MOLECULAR WEIGHT HEPARIN Dose on actual body weight and avoid dose capping 1mg/kg BID is preferred for enoxaparin Heparin should not be dose capped Monitoring is likely not required J Thromb Haemost 2005; 3:

6 Obesity is an independent risk factor for VTE 38,000 cases of VTE related to obesity in 2000 Less than 25% of patients achieve adequate anti-xa levels p<0.01 J Thromb Thrombolysis (2016) 41: Obes Surg 12:19 24 Guidelines are unclear Alternative regimens Enoxaparin 0.5mg/kg daily or twice daily Enoxaparin 40mg twice daily Heparin 7500 units three times daily Monitoring anti-xa No correlation exists with thrombosis or bleeding J Thromb Thrombolysis (2016) 41: Thromb Haemost 111:88 93 Retrospective cohort of patients > 100kg High dose prophylaxis Enoxaparin 40mg BID Heparin 7500 units Q8H Primary outcome: in-hospital VTE Non-Surgical Patients > 100kg (n=9241) BMI > 40 kg/m 2 (n=3928) BMI < 40 kg/m 2 (n=5313) Obes Surg 12:19 24 Retrospective review of 481 bariatric surgery patients All patients treated with standardized prophylaxis regimen Primary endpoint of DVT or PE 6 month follow-up Enoxaparin 30mg Q12 (n=92) Primary and revisional bariatric patients Enoxaparin 40mg Q12h (n=389) VTE PPX IN OBESITY Population Prophylaxis VTE P value BMI < 40 kg/m Standard 1.54 High-dose 1.88 BMI > 40 kg/m Standard 1.48 High-dose 0.77 NNT: 140 No difference in bleeding events Thromb Haemost 111:

7 Standard dosing is often insufficient in morbidly obese patients TREATMENT OF HIT 3 phases of treatment Discontinuation of heparin products Anti-Xa assays have a limited role Patients with a BMI > 40 kg/m 2 should receive high dose thromboprophylaxis Enoxaparin 40mg subcutaneous twice daily Heparin 7500 units subcutaneous three times daily Acute parenteral anticoagulation Argatroban, bivalirudin, fondaparinux Oral therapy (vitamin K antagonist) following platelet recovery HIT with thrombosis: 3 months Isolated HIT: 4 weeks CHEST 2012; 141(2)(Suppl):e495S e530s TREATMENT OF HIT Novel Therapies for Heparin Induced Thrombocytopenia TRADITIONAL THERAPIES Argatroban Monitoring / dosing complications Cost Fondaprinux Contraindicated in renal impairment Subcutaneous administration Warfarin Complicated bridging process DOAC THERAPY Oral Active immediately Less expensive Monitoring not required Ease of conversion to other anticoagulants Ann Pharmacother Jun;49(6): HEPARIN INDUCED THROMBOCYTOPENIA (HIT) Observed in 1 to 5% of patients Occurs as a result of heparin-platelet factor 4 complex generated IgG antibodies Heparin-PF-4 complex mediated IgG Platelet activation & aggregation DOACS IN HIT DABIGATRAN, RIVAROXABAN, APIXABAN 12 patients treated with argatroban and DOAC therapy Dabigatran 150mg BID (2) Rivaroxaban 20mg daily (7) Apixaban 5mg BID (3) DOAC continued for a minimum of 3 months Thrombosis and thrombocytopenia Platelet activation occurs without the need for heparin in acute HIT Ann Pharmacother Jun;49(6): Thrombin production Consumption of platelets J Am Coll Cardiol 63:A2096 DOAC therapy well tolerated No recurrent VTE or hemorrhagic events observed 7

8 DOACS IN HIT DABIGATRAN, RIVAROXABAN, APIXABAN Prospective cohort of 22 patients treated with argatroban and DOAC therapy Dabigatran 150mg BID (6) Rivaroxaban 20mg daily (11) Apixaban 5mg BID (5) 7 patients experienced VTE (4 lower; 1 upper; 2 superficial) No recurrent VTE, bleeding, or limb loss occurred 6 patients died at 19 months (non-vte related) CONTROVERSIES AND UNANSWERED QUESTIONS IN ANTICOAGULANT THERAPY Thromb Res Apr;135(4):607-9 Kyle Davis, PharmD, BCPS Treatment of HIT is complicated DOACs may provide more convenient alternatives HIT is associated with a poor prognosis CONCLUSIONS The anti-xa assay has several advantages over APTT when monitoring heparin Routine laboratory assays provide some benefit when monitoring DOACs Dose capping should not be recommended with heparin and LMWH DOACs may be a safe and effective alternative to standard HIT treatment regimens 8