9/28/2020 Use of Direct-acting Oral Anticoagulants in Heparin- Induced Thrombocytopenia Jennifer Austin Szwak, PharmD, BCPS Clinical Pharmacy Specialist, Internal Medicine University of Chicago Medicine Financial Disclosure & Conflict of Interest • No relevant conflicts of interest Learning Objectives • Describe the pathophysiology of heparin-induced thrombocytopenia (HIT) • Compare guideline recommendations for the treatment of HIT from the American College of Chest Physicians and American Society of Hematology • Review current literature describing the use of direct-acting oral anticoagulants (DOACs) in HIT 1 9/28/2020 Heparin-Induced Thrombocytopenia (HIT) • Immune-mediated reaction • Hypercoaguable state • Occurs in approximately <0.1 – 7% of patients exposed to heparins • 35 – 50% of patients will develop new or recurrent thrombosis if not treated • Typically manifests as a significant drop in platelets after heparin exposure New Engl J Med 2006; 355(8):809-17 Blood 2012; 120(20): 4160-67 Pathophysiology IgG antibody heparin Heparin-PF4 complex platelet Immune PF4 complexes Circulation 2005;111:2671-83. Testing Algorithm Suspected HIT Assess 4Ts Score Blood Adv 2018; 2(22): 3360-92 2 9/28/2020 4Ts Score Category 2 points 1 point 0 points Thrombocytopenia Platelet count fall >50% Platelet count fall 30-50% Platelet count fall <30% or and platelet nadir ≥ 20 or platelet nadir 10-19 platelet nadir <10 Timing of platelet count Clear onset days 5-10 or Consistent with days 5-10, Platelet count ≤4 days fall platelet fall ≤1 day with but not clear; onset after without recent heparin prior heparin exposure day 10; or fall ≤1 day with exposure within 30 days prior heparin exposure in previous 30-100 days Thrombosis or other New thrombus Progressive or recurrent None sequelae (confirmed); skin thrombosis; non- necrosis; acute systemic necrotizing skin lesions; reaction post IV heparin suspected thrombosis OTher causes of None Possible Definite thrombocytopenia Blood 2012; 120(20): 4160-67. Testing Algorithm 4Ts Score Intermediate Low (1-3) High (6-8) (4-5) No HIT Obtain laboratory immunoassay testing Blood Adv 2018; 2(22): 3360-92 PF4 Enzyme-linked immunoassay (ELISA) • Detects binding of patient antibodies to PF4 complex • Binding causes color change • Most assays measure IgG, IgM, and IgA antibodies • Measuring only IgG antibodies increases specificity of test CHEST 2005; 127: 35S-45S 3 9/28/2020 Evaluation of PF4 Result PF4 OD Result Likelihood of HIT Interpretation < 0.4 0 Negative 0.4 – 1 ~3% Lab dependent 1 – 1.4 ~15 – 20% Positive 1.4 – 2 ~50% Positive > 2 ~90% Positive CHEST 2005; 127: 35S-45S Testing Algorithm Immunoassay Positive Negative Stop non-heparin Obtain functional product & resume assay heparin, if indicated Blood Adv 2018; 2(22): 3360-92 Serotonin Release Assay (SRA) • Functional assay • Platelets are “washed” resulting in high sensitivity to activation by HIT serum • At pharmacologic heparin concentrations, high platelet activation occurs releasing radiolabeled serotonin CHEST 2005; 127: 35S-45S 4 9/28/2020 Testing Algorithm SRA Positive Negative Stop non-heparin HIT Likely product & resume heparin, if indicated Blood Adv 2018; 2(22): 3360-92 Stages of HIT Suspected Subacute Subacute Remote Acute HIT HIT HIT A HIT B HIT Platelet ↓ ↓ Normal Normal Normal count Functional ? + + - - assay Immuno- ? + + + - assay Blood Adv 2018; 2(22): 3360-92 Treatment of HIT 5 9/28/2020 Standard HIT Treatment • Therapeutic anticoagulation with a non-heparin agent • If taking a vitamin K antagonist (VKA) at the time of HIT onset, administer intravenous vitamin K with non-heparin agent • Do NOT initiate VKA before platelet recovery (usually ≥ 150x 109/L) • Non-heparin anticoagulant should overlap for a minimum of 5 days and until INR is in goal range • Treatment duration: • No thrombosis: at least until platelet recovery & not longer than 3 months • HIT with thrombosis (HITT): 3-6 months CHEST 2012; 141(2):e495S–e530S Blood Adv 2018; 2(22): 3360-92 2012 ACCP Guidelines • Non-heparin anticoagulants (argatroban, lepirudin, or danaparoid) are recommended over heparin, low molecular weight heparins, or initiation/continuation of VKA (Grade 1C) • Argatroban is preferred over other agents in HITT (Grade 2C) CHEST 2012; 141(2):e495S–e530S 2018 ASH Guidelines • When selecting a non-heparin anticoagulant, argatroban, bivalirudin, danaparoid, fondaparinux or DOACs are suggested (+) • Argatroban or bivalirudin recommended if critically ill, increased bleeding risk, potential need for urgent procedures, or life-/limb-threatening thromboembolism • Fondaparinux or DOACs reasonable choice if clinically stable and average bleeding risk • In subacute HIT A (normal platelets, positive immunoassays), DOACs are suggested over VKA (+++) +: conditional recommendation, low certainty in evidence about effects +++: conditional recommendation, moderate certainty in evidence about effects Blood Adv 2018; 2(22): 3360-92 6 9/28/2020 Recommendations re: DOACs 2012 ACCP Guidelines 2018 ASH Guidelines • No published evidence to • DOACs may be used in clinically support the use of DOACS for stable patients with average treatment of HITT bleed risk • No recommendations • Similar contraindications to use in VTE should be applied • Rivaroxaban has the most published data CHEST 2012; 141(2):e495S–e530S Blood Adv 2018; 2(22): 3360-92 Why the difference? DOACs in HIT 7 9/28/2020 DOACs & Platelets • No platelet activation in presence of HIT antibodies • No release of PF4 from resting or activated platelets • No interactaction with PF4 Br J Haematology 2008; 143: 92-99 Blood 2012; 119(5): 1248-55 Clin Appl Thromb Hemost 2013; 19(5):482-7 Sharifi et al, 2015 Study design Retrospective identification of patients, prospective follow-up HIT definition - History of recent heparin exposure + 50% reduction of platelet count or platelets <100 without other explainable causes - PF4 sent for all cases - SRA only sent if PF4 negative Treatment - All heparin discontinued - Argatroban 0.3-0.5mcg/kg/min (goal aPTT 50-90) - DOAC initiated 2h after argatroban discontinuation Outcomes - Mortality - Venous or arterial thrombosis - Limb loss - Bleeding n = 22 Thromb Res 2015;135(4):607–9. Sharifi et al, 2015 Platelet count, Baseline: 168.8 x109 (87.1) mean (SD) Nadir: 82.1 x109 (38.6) Discharge: 188.4 x109 (52.5) HIT testing 20/22 (91%) PF4+ Associated 5 patients with DVTs & 2 superficial thrombi thrombosis Initial treatment - All patients received argatroban - Mean duration 32 ± 4 hours Oral treatment - Dabigatran 150mg BID (n = 6)* - Rivaroxaban 20mg daily (n = 11)* - Apixaban 5mg BID (n = 5) Treatment - Minimum 3 months duration - 82% extended to at least 6 months Outcomes - No deaths attributed to thrombotic events - No bleeding Thromb Res 2015;135(4):607–9. 8 9/28/2020 Sharifi et al, 2015 Pros Cons • Extended prospective follow up • HIT diagnosis inconsistent with • Several patients with HITT guideline recommendations • Platelets recovered with early • Specifics about patients are switch to DOAC agents lacking • No recurrent events or bleeding • Apixaban and rivaroxaban dosing are lower than typical VTE dosing Kunk et al, 2017 Study Design Retrospective chart review HIT definition Positive SRA Treatment Argatroban or bivalirudin infusion until platelets ≥ 50 x 103/µL Transitioned to rivaroxaban or apixaban Exclusion Patients without clinic follow up or ability to capture bleeding & thrombotic events Outcomes Recurrent thrombotic events Major bleeding events Days to platelet recovery n = 12 J Thromb Thrombolysis 2017;43(1):79–85. Kunk et al, 2017 Platelet count, Nadir: 49 x103/µL (16-147) median (range) HIT testing PF4+: 9/12 (75%) SRA+: 12/12 (100%) Associated 9 patients with thrombi at time of diagnosis thrombosis Initial treatment All patients received argatroban (n = 6) or bivalirudin (n = 6) Duration: 6 days (range 2 – 25 days) Oral treatment Rivaroxaban (n = 2) Apixaban (n = 10) Treatment No HITT: 1 – 2 months duration HITT: minimum 3 months (range 3 – 16 months) Outcomes No recurrent thrombi 2 major bleeding events (GI bleed, hemoptysis) J Thromb Thrombolysis 2017;43(1):79–85. 9 9/28/2020 KunkSummaryet al, 2017 Pros Cons • Follow up in all patients • DOAC dosing strategy not • Several patients with HITT described • No recurrent events • Platelets at time of transition to DOAC unclear • Broad range of parenteral agent use • 2 major bleeding events Davis et al, 2017 Study Design Retrospective chart review HIT definition 4Ts score ≥ 4 Positive PF4 (OD > 0.4) or positive SRA Treatment Argatroban or bivalirudin infusion until platelets ≥ 50 x 103/µL Transitioned to rivaroxaban or apixaban Exclusion Negative SRA History of HIT Admission <48 hours Outcomes Newly diagnosed venous or arterial thromboembolism, gangrene, or amputation for critical leg ischemia during hospitalization following DOAC initiation Major bleeding 30 day mortality Time to platelet recovery (>150 x 109/L or baseline) n = 12 Eur J Haematol. 2017;99:332–335. Davis et al, 2017 Platelet count, Nadir: 58 x103/µL (12-91) median (range) Time to platelet recovery: 7.5 days (3 – 14) HIT testing Mean PF4 OD: 1.66units (range 0.24 – 3.34) SRA+: 4/12 (33%) Associated 5 patients with thrombi at time of diagnosis thrombosis Parenteral 7 patients received argatroban (range: 24 – 530 hours) treatment 5 patients did not receive parenteral therapy Oral treatment Apixaban 10mg BID (n = 1) Apixaban 5mg BID (n = 7) Apixaban 2.5mg BID (n = 1) Rivaroxaban 15mg BID (n = 3) Treatment Mean inpatient DOAC treatment: 9.3days (range: