9/28/2020 1 Use of Direct-Acting Oral Anticoagulants in Heparin- Induced Thrombocytopenia

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

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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

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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

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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

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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

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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

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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

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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.

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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.

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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: 1-32 days) duration Total duration not described Outcomes No recurrent thrombi No major bleeding Eur J Haematol. 2017;99:332–335.

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Davis Summaryet al, 2017

Pros Cons • Several patients with HITT • Follow up only during inpatient • All patients had platelet hospitalization recovery • DOAC dosing inconsistent with • No recurrent events VTE dosing recommendations • Platelets at time of transition to DOAC unclear • Total duration of therapy not described

Linkins et al, 2016

Study Design Multicenter, single-arm, prospective cohort HIT definition 4Ts score ≥ 4 Positive SRA Treatment Rivaroxaban 15mg BID until platelet recovery (or at least 21 days if HITT) then 20mg daily Exclusion Pregnant or nursing History of HIT or enrollment in past 100 days Mechanical heart valve Severe renal disease or hepatic disease associated with coagulopathy Outcomes New symptomatic venous or arterial thromboembolism at 30 days Major bleeding Time to platelet recovery (>150 x 109/L or baseline) n = 12

J Thromb Haemost2016;14:1206-10.

Linkinsetet al al, 2016

Platelet count, Nadir: 56 x103/µL (21 – 300) median (range) Time to platelet recovery: 7 days (3 – 29) HIT testing SRA+: 12/12 (100%) Associated 6 patients thrombosis Parenteral 6 patients received fondaparinux (2-3 days) treatment 1 patient received danaparoid (1 day) 5 patients did not receive parenteral therapy Oral treatment Rivaroxban 15mg BID until platelet recovery (or 21 days in HITT) then 20mg daily Treatment 371 total days of rivaroxaban exposure duration Outcomes 1 recurrent VTE 1 bleeding event

J Thromb Haemost2016;14:1206-10.

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Linkins et al, 2016

Pros Cons • Prospective study • Use of fondaparinux • Strong HIT definition • 1 thrombus & 1 bleed • 50% with HITT • Consistent rivaroxaban dosing

Warkentin et al, 2017

Study Design Retrospective chart review HIT definition 4Ts score ≥ 4 Positive PF4 & SRA Treatment At the discretion of individual physicians Outcomes New symptomatic venous or arterial thromboembolism at 30 days Major bleeding Time to platelet recovery (>150 x 109/L or baseline)

n = 16

Blood 2017;130(9):1104-13.

Warkentin et al, 2016

Group A1 A2 B C

Primary Parenteral Parenteral DOAC DOAC Treatment agent agent

Platelets at Platelets < 150 x < 150 x > 150 x DOAC never <150 109/L 109/L 109/L initiation x 109/L

Blood 2017;130(9):1104-13.

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Group A1 Characteristics (n = 7)

Platelet count, Before rivaroxaban: 56 x103/µL (25 – 107) median (range) Time to platelet recovery: 4 days (3 – 17) HIT testing 4Ts score: 5 – 7 Median PF4 OD: 2.15 (range 1.66 – 3.07) SRA+: 12/12 (100%) Associated 3 VTE thrombosis Parenteral None treatment Oral treatment Rivaroxaban 15mg BID x 21 days, then 20mg daily (4) Rivaroxaban 20mg daily (2) Rivaroxaban 15mg BID x 6 days, then 20mg daily (1) Treatment ≥ 30 days duration Outcomes No recurrent VTE No bleeding event Blood 2017;130(9):1104-13.

Group A2 Characteristics (n = 1)

Platelet count, Before rivaroxaban: 415 x103/µL median (range) Time to platelet recovery: N/A HIT testing 4Ts score: 6 Median PF4 OD: 2.17 Associated Bilateral adrenal hemorrhage thrombosis Parenteral None treatment Oral treatment Rivaroxaban 10mg daily Treatment ≥ 30 days duration Outcomes No recurrent VTE No bleeding event

Blood 2017;130(9):1104-13.

Group B Characteristics (n = 2)

Platelet count, Before rivaroxaban: 68.5 x103/µL (64 – 73) median (range) Time to platelet recovery: 33.5 days (7 – 60) HIT testing 4Ts score: 6 – 8 Median PF4 OD: 2.29 (range 2.10 – 2.48) SRA+: 12/12 (100%) Associated 1 patient thrombosis Parenteral Fondaparinux x 1-4 days treatment Oral treatment Rivaroxaban 15mg BID x 21 days, then 20mg daily x 3 days, then 10mg daily (1) Rivaroxaban 15mg BID x 12 weeks, then 20mg daily (1) Treatment ≥ 30 days duration Outcomes No recurrent VTE No bleeding event

Blood 2017;130(9):1104-13.

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Group C Characteristics (n = 6)

Platelet count, Before rivaroxaban: 197.5 x103/µL (259 – 361) median (range) HIT testing 4Ts score: 5-6 Median PF4 OD: 2.45 (range 1.11 – 2.89) SRA+: 6/6 (100%) Associated 1 patient thrombosis Parenteral Argatroban x3 days then fondaparinux x 51 days (1) treatment Fondaparinux x 5 – 11 days (5) Oral treatment Rivaroxaban 10mg daily (3) Rivaroxaban 20mg daily (2) Rivaroxaban 15mg BID x 12 weeks, then 20mg daily (1) Treatment ≥ 30 days (5) duration 21 days (1) Outcomes No recurrent VTE No bleeding event Blood 2017;130(9):1104-13.

Warkentin et al, 2016

Pros Cons • All confirmed SRA positive • Different rivaroxaban dosing • Categorization of HIT groups strategies • No recurrent events or bleeding • Use of fondaparinux is not consistent with practice at many institutions

Ong et al, 2017

Study Design Retrospective chart review HIT definition 4Ts score ≥ 4 Positive PF4 Treatment Rivaroxaban without preceding parenteral agent Outcomes Progressive or new thrombosis Limb ischemia leading to amputation Time to platelet recovery

n = 9

Ann Hematol 2017;96(3):525-27.

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Ong et al, 2017

Platelet count, Nadir: 28 x103/µL (6 – 71) median (range) Time to platelet recovery: 8 days (5 – 41) HIT testing Mean PF4 OD: 2.34 units (range 1.13 – 3.21) Associated 8 patient with VTE thrombosis 1 patient with worsening pulmonary embolism Oral treatment Rivaroxaban 10mg daily (5) Rivaroxaban 15mg BID x 21 days then 20mg daily (3) Rivaroxaban 15mg BID (1) Treatment 13 days – 39 months duration Outcomes No recurrent thrombi No amputations No major bleeding

Ann Hematol 2017;96(3):525-27.

OngDavis et Summary al, 2017

Pros Cons • Follow up in all patients • SRAs not available • Several patients with HITT • Patients transitioned to warfarin • No recurrent events • Total duration not clear in patients switching agents

Nasiripour et al, 2019

Study Design Retrospective chart review HIT definition 4Ts score ≥ 4 Exclusion Severe renal insufficiency (CrCl <15mL/min) Hepatic impairment (Child Pugh B & C) Mechanical heart valves Active bleeding Extremes of weight (<50kg or >120kg) Inappropriately dose adjusted based on renal function Treatment Dabigatran 110mg BID or 75mg BID if CrCl 15 – 30mL/min Outcomes New symptomatic venous or arterial thrombosis Hemorrhagic events

n = 40 J Clin Pharmacol 2019;59(1):107-111.

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Nasiripour et al, 2019

Platelet count, At time of HIT diagnosis: 80 x103/µL (35 – 160) mean (range) Time to platelet recovery: 7.4 days HIT testing 4Ts score > 6: 23 (82.5%) Associated Not reported thrombosis Oral treatment Dabigatran 110mg BID (33) Dabigatran 75mg BID (7) Treatment Not reported duration Outcomes 1 new thrombus No major bleeding

J Clin Pharmacol 2019;59(1):107-111.

NasiripourDavis Summaryet al, 2019

Pros Cons • Largest cohort of patients • No confirmatory testing • Standardized dosing practice • Incidence of HITT not reported • Duration of treatment not reported • Dosing of dabigatran not consistent with FDA approved dosing

Summary of case reports (n = 13)

Platelet count, Nadir: 32 x103/µL (16 – 161) median (range) HIT testing 4Ts score ≥ 6: 5 (38%) Positive PF: 12 (92%) Positive functional HIT assay: 5 (38%) Associated 10 patients with VTE (77%) thrombosis Parenteral Fondapariunx (6) Danaparoid (1) treatment Argatroban (2) Bivalirudin (1) Oral treatment Rivaroxaban 15mg BID x 21 days then 20mg daily (5) Dabigatran 110mg BID (1) Rivaroxaban 20mg BID (1) Apixaban 5mg BID (1) Rivaroxaban 20mg daily (1) Apixaban 2.5mg BID (1) Rivaroxaban 15mg BID (1) Rivaroxaban dose not stated (2) Outcomes No thromboembolic events No major bleeding

References 17 - 29

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Summary of All Data

Rivaroxaban Dabigatran Apixaban

Total patients, n 63 46 25

DOAC as initial 27 (43%) 40 (87%) 4 (16%) treatment, n (%)

Thrombotic events, 1 (2%) 1 (2%) 0 (0%) n (%)

Bleeding events, 2 (3%) 0 (0%) 1 (4%) n (%)

Patient Case #1

67YO male underwent cardiac surgery where he received UFH during and following the procedure.

Day 1 Day 6 Platelets 237 Platelets 89

Patient Case #2

45YO female admitted with worsening calf pain after receiving enoxaparin for a DVT that was diagnosed 7 days ago. An ultrasound shows extension of the known DVT.

VTE diagnosis Hospital Admission Platelets 180 Platelets 71

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Take Home Points

• DOACs can be considered in patients with HIT • Strongest data is with rivaroxaban • Most data supports the use of VTE dosing • Timing of initiation and duration of treatment depends on clinical status of patient

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