Overview of Target-Specific Oral Anticoagulants (TSOACs)

Overview of Target-Specific Oral Anticoagulants (TSOACs)

Overview of Target-Specific Oral Anticoagulants (TSOACs) The Blood Thins and the Plot Thickens American College of Physicians Annual Scientific Meeting November 7, 2014 Allison Burnett, PharmD, CACP, PhC Clinical Assistant Professor- UNM College of Rx Team Lead- Inpatient Anticoagulation Services University of New Mexico Hospital Disclosures Anticoagulation Forum Board member Honoraria

Society of Hospital Medicine (SHM) Honoraria Island Peer Review Organization (IPRO) Honoraria Practical Management of TSOACs Appropriate patient selection Laboratory measurement Peri-procedural management Switching between agents Management of severe bleeding

Practical Management of TSOACs Appropriate patient selection Laboratory measurement Peri-procedural management Switching between agents Management of severe bleeding Case 1 Which of the following patients would be considered a good candidate for TSOAC therapy? A. 64-year-old male with a St. Judes mechanical mitral valve B. 65-year-old female with diabetes & hypertension (both well-controlled with medication), normal kidney function and new onset atrial fibrillation C. 37-year-old female with end-stage renal disease, on hemodialysis, who has thrombosed her dialysis fistula D. 54-year-old male with a history of recurrent VTE and labile INR due to non-compliance with warfarin therapy TSOAC: Mechanism of Action

Adapted from Weitz JI, Bates SM. J Thromb Haemost 2005; 3: 1843-53. Agent EU US Canada Rivaroxaban (Xarelto) NVAF VTE PPX VTE TX ACS NVAF VTE PPX

VTE TX NVAF VTE PPX VTE TX Apixaban (Eliquis) NVAF VTE PPX NVAF VTE PPX VTE TX NVAF VTE PPX Dabigatran (Pradaxa)

NVAF VTE PPX VTE TX NVAF NVAF VTE PPX Edoxaban (Lixiana) VTE TX Japan VTE PPX Siegal DM, et al. J Thromb Thrombolysis 2013; 35: 391-98.

TSOACs: Approved Indications ACS = acute coronary syndrome; NVAF = non-valvular atrial fibrillation; PPX = prophylaxis; TX = treatment; VTE = venous thromboembolism Comparison of Oral Anticoagulants Agent Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban IIa, VIIa, IXa, Xa IIa

Xa Xa Xa 4-5 days 1.5-3 h 2-4 h 1-3 h 1-2 h Half-life 40 h

12-17 h 5-9 h 9-14 h 9-11 h Renal elim. None 80% 33% 25% 35-50% Dialyzable

No Yes No No No Interactions Many P-gp 3A4, P-gp 3A4, P-gp

3A4, P-gp Monitoring Yes No No No No Vitamin K No No No

No INR aPTT (qual) PT (qual) No data PT (qual) Target Peak effect Antidote Lab measure P-gp = p glycoprotein 3A4 = cytochrome P450 3A4

qual = qualitative Cove CL, Hylek EM. J Am Heart Assoc. 2013; 2:e000136. TSOACs: Advantages Improved pharmacokinetic/pharmacodynamic profile Rapid onset/offset of action Fewer dietary and drug interactions Wide therapeutic window allows fixed dosing No need for routine monitoring Greater convenience and patient satisfaction Improved safety profile

Potentially more cost-effective Bauer KA. ASH Education Book 2013; 1:464-470 Ruff CT, et al. Lancet 2013; 383 (9921): 955-62 TSOACs: Disadvantages Dose reduction or avoidance in kidney impairment Lack of flexibility in dosing Short half-life mandates strict compliance Limited availability of lab assays to measure anticoagulant effect

Lack of antidote Higher drug acquisition costs Fewer studied/approved indications (e.g., valves, ACS) Bauer KA. ASH Education Book 2013; 1:464-470 Majeed A, et al. Circulation 2013; 128)21): 2325-32 TSOAC: Dosing Varies by:

TSOAC Indication Country May require adjustment for: Renal impairment Age Weight Drug interactions A combination of the above TSOACs: Dosing (FDA Labeling) Apixaban Non-valvular atrial fibrillation 5 mg PO BID 2.5 mg PO BID* VTE prophylaxis

(orthopedic) 2.5 mg PO BID VTE treatment and prevention of recurrence N/A Dabigatran Rivaroxaban 150 mg PO BID 75 mg PO BID* 20 mg PO daily 15 mg PO daily*

CrCl <15 mL/min Avoid use CrCl <15 mL/min Avoid use N/A 10 mg PO daily CrCl <30 mL/min Avoid use CrCl <30 mL/min Avoid use 150 mg PO BID after 5-10 days of parenteral anticoagulation 15 mg PO BID x 21 days,

then 20 mg PO daily CrCl <30 mL/min Avoid use CrCl <30 mL/min Avoid use * Adjusted for renal impairment, drug interactions, age, low weight or a combination of these factors Treatment doses of rivaroxaban should be taken with largest meal of the day Appropriate Patient Selection No contraindication to TSOAC e.g., pregnancy, mechanical valve Good compliance history or highly likely to be compliant with

medication and follow-up plan Adequate organ function Lack of significant drug-drug interactions with TSOACs (e.g. azoles, macrolides, antiepileptics, protease inhibitors, antacids, several cardiac medications) Confirmed ability to obtain medication longitudinally Ageno W, et al. J Thromb Haemost 2013; 11: 177-9. Practical Management of TSOACs Appropriate patient selection Laboratory measurement Peri-procedural management

Switching between agents Management of severe bleeding Case 2 A 46-year-old male on rivaroxaban x 2 weeks for acute PE presents to the ED with severe GI bleed. Labs and vitals: SCr 2.3 mg/dL, Hgb/Hct 4.2/12, BP 90/50, HR 120s. Which of the following labs would be most helpful in assessing for presence of rivaroxaban? A. Ecarin clotting time (ECT) B. Prothrombin time (PT) C. Activated partial thromboplastin time (aPTT) D. Thrombin time (TT) Measurement of TSOACs Increased specificity for target inhibition

Predictable pharmacokinetic and pharmacodynamic response Minimal dietary effect Less intrasubject and intersubject variability Wide therapeutic index Do not require routine monitoring Dose is not adjusted based on laboratory measurements No therapeutic ranges are provided

Measurement of TSOACs When might measurement of a TSOAC be indicated? Determine presence and quantity of drug Urgent or emergent invasive procedure Neuraxial anesthesia Major trauma Potential thrombolysis in acute thrombosis Assessing compliance Hemorrhagic or thrombotic complications Assess drug accumulation Diminished/changing renal function Hepatic impairment Accidental or intended overdose Drug interactions Adcock DM. ASH Education Book 2012 ; 2012 (1): 460-65. Garcia D et al. J Thromb Haemost 2013; 11: 245-52. Tripodi A. Blood 2013; 121: 4032-35.

Measurement of TSOACs Routine coagulation assays Activated partial thromboplastin time (aPTT) Prothrombin time (PT) Helpful in determining relative drug concentration (qualitative) Readily available in most reference labs Specialty coagulation assays Thrombin time (TT) Dilute thrombin time (dTT) Ecarin clotting time (ECT) Chromogenic Anti-Xa Determine measured drug concentration (quantitative) Not readily available nor standardized Research or investigational use only at this point Measurement of TSOACs

Effect of TSOAC on Coagulation Assays Test Dabigatran aPTT* Rivaroxaban Apixaban / no effect / no effect PT*

TT No effect No effect ECT No effect No effect No effect

Anti-Xa** *Variability by reagent/instrumentation **Drug-specific TT = thrombin time ECT = ecarin clotting time Hillarp AJ, Thromb Haemost 2011;9:133-9. Funk DM, Hematology 2012:460-465. Frost et al, Br J Clin Pharmacol 2012;75:476. Garcia D, et al. J Thromb Haemost 2013; 11: 245-52. Measurement of TSOACs Rules of Thumb Dabigatran

With 150 mg twice daily dosing, peak aPTT ~2x control Elevated aPTT = drug present Normal aPTT = minimal drug effect Normal thrombin time (TT) = absence of drug effect PT should not be used (relatively insensitive to dabigatran) Rivaroxaban With rivaroxaban 20 mg daily, peak PT ~1.5x control Elevated PT = drug present Elevated anti-Xa (drug-specific) = drug present Normal PT = minimal drug effect aPTT should not be used (some reagents relatively insensitive) Practical Management of TSOACs Appropriate patient selection Laboratory measurement Peri-procedural management Switching between agents Management of severe bleeding

Case 3 A 62-year-old male with atrial fibrillation (CHADS2 score of 2 for DM, HTN) on a TSOAC for stroke prevention is scheduled to undergo total knee replacement in a few weeks. Labs: SCr 0.7 mg/dL, weight 83 kg, Hgb 10.2, Hct 31 Which of the following describes the best course of action for his periprocedural anticoagulation? A. Do not interrupt TSOAC therapy for this procedure B. Hold TSOAC for 2-3 half-lives prior to this low bleed risk procedure C. Hold TSOAC for 4-5 half-lives prior to this high bleed risk procedure D. Hold TSOAC for 5 days prior to procedure and use LMWH as bridging therapy Peri-Procedural Management: TSOACs ~250,000 patients annually in the US evaluated for anticoagulation management around elective procedures Rapid onset/offset of TSOACs precludes need for peri-operative

bridging with heparin or LMWH Key question: Does anticoagulation need to be interrupted? Timing of cessation and resumption of TSOAC is based on: Patients renal function Half-life of TSOAC Type of procedure and anesthesia Spyropolous AC, et al. Blood 2012; 120(15): 2954-62. Assessing Thrombotic Risk Spyropolous AC, et al. Blood 2012; 120(15): 2954-62 Assessing Bleed Risk

Baron TH, et al. N Engl J Med 2013; 368: 2113-24. Peri-Procedural Management: TSOACs Management of Anticoagulation in the Peri-procedural Period (MAP) Tool Available at http://qio.ipro.org/drug-safety/drug-safety-resources or http://excellence.acforum.org/ Risk Assessment High Bleed Risk Low Bleed Risk High thromboembolic risk Moderate thromboembolic risk Low thromboembolic risk

Interrupt TSOAC Consider interrupting TSOAC Interrupt TSOAC Minimal Bleed Risk Do not interrupt TSOAC Peri-Procedural Management: TSOACs Cessation of TSOAC

Dependent on patients renal function and half-life of TSOAC Half-life ranges from 6-17 hours, depending on TSOAC Will be prolonged with renal impairment May almost double in severe impairment May require longer pre-op hold time Dependent on type of procedure Low bleed risk: hold for 2-3 half-lives High bleed risk: hold for 4-5 half lives Stangier J, et al. Clin Pharmacokinet 2010; 49(4): 259-68. Spyropolous AC, et al. Blood 2012; 120(15): 2954-62. Peri-Procedural Management: TSOACs Resumption of TSOAC

TSOACs have rapid onset of anticoagulant effect (~1-4 hours) Analogous to using LMWH Caution with resuming too soon or too aggressively Timing of resumption dependent on type of procedure Low bleed risk: resume 24 hours post-op High bleed risk: resume 48-72 hours post-op May consider step-up approach Lower or prophylactic dose of TSOAC for initial 24-48 hours If tolerated, increase to treatment dose TSOAC at 48-72 hours Spyropolous AC, et al. Blood 2012; 120(15): 2954-62. Peri-Procedural Challenges May need to confirm absence of anticoagulant effect Emergent procedures Planned use of spinal or epidural anesthesia Ensure use of appropriate lab parameter

Delayed resumption of TSOAC Patient unable to take PO post-procedure Concern for impaired gastrointestinal absorption (e.g., post-op ileus) Epidural or spinal anesthesia Consider use of parenteral anticoagulant until patient can be appropriately switched to TSOAC Spyropolous AC, et al. Blood 2012; 120(15): 2954-62. Practical Management of TSOACs Appropriate patient selection Laboratory measurement Peri-procedural management Switching between agents Management of severe bleeding Case 4 A 71-year-old female on dabigatran for NVAF (CHA2DS2VASc = 6) and

recurrent VTE was admitted for ACS and emergently taken to the cath lab for percutaneous coronary intervention (PCI). She was found to have multivessel disease and had 2 drug-eluting stents placed, which will require dual antiplatelet therapy. Which of the following antithrombotic strategies would be the best option for her? A. Resume dabigatran along with dual antiplatelet therapy indefinitely B. Stop dabigatran. Overlap LMWH and warfarin until INR >2, along with antiplatelet therapy D. Stop anticoagulation and continue only dual antiplatelet therapy Switching Between Anticoagulants Reason for switching from parenteral to oral anticoagulant Facilitate longer-term outpatient management

Reasons for switching from warfarin to TSOAC Drug intolerance Therapeutic failure Patient preference Reasons for switching from TSOAC to warfarin Drug intolerance Therapeutic failure Patient preference New comorbidity or contraindication Worsening renal function Mechanical heart valve Acute coronary syndrome (ACS) requiring dual antiplatelet therapy Abo-Salem E, et al. J Thromb Thrombolysis 2014; 37: 372-79. Switching Between Anticoagulants Can place patients at undue risk for adverse events e.g., bleeding or thrombosis

Requires a carefully constructed and thoughtful approach Should be based on: Pharmacokinetic profile of each anticoagulant Appropriate laboratory assessment of patients coagulation status Patients renal function Abo-Salem E, et al. J Thromb Thrombolysis 2014; 37: 372-79. Switching Between Anticoagulants Unfractionated heparin Short half-life precludes need for lag time until alternative anticoagulant is initiated

TSOACs and SQ injectables (LMWH, fondaparinux) Longer half-life requires lag time until alternative anticoagulant is initiated Start alternative anticoagulant when the next dose of original anticoagulant would be due Warfarin Extremely long half-life requires confirmed offset via INR Slow onset may require overlap of rapid-acting anticoagulant Switching Between Anticoagulants Practical Management of TSOACs Case 5 A 62-year-old female on apixaban 2.5 mg PO BID for VTE prophylaxis after a total hip arthroplasty presents to the ED with mild hematuria. She is hemodynamically stable. When asked, she states she last took

her apixaban yesterday morning, and missed her evening dose due to not feeling well. What are options for managing her bleeding episode? A. Hemodialysis to remove the apixaban B. Oral activated charcoal to remove the apixaban C. Concentrated factors (PCC, aPCC, rFVIIa) to reverse apixaban D. Supportive care and investigate for source of the bleed Management of Severe Bleeding: TSOACs General approaches Hold anticoagulation Determine time of last ingestion Tincture of time (short half-lives) Fluid resuscitation to promote renal excretion Transfusion of blood products Attempt to identify and address source of bleed Mechanical compression Have specialty services on standby

If inadequate response, consider reversal strategies Seigal DM, Cuker A. Drug Discov Today 2014. [Epub ahead of print] PMID: 24880102. Hierarchy of Evidence: Reversal of TSOACs Concentrated Factors for TSOAC Reversal Clinical outcome data on the efficacy of PCC, aPCC and rFVIIa for the reversal of TSOACs are lacking Available evidence is limited (healthy human volunteers, animal models, in vitro studies) with conflicting results

These agents may be considered in addition to maximum supportive measures in patients with severe/life-threatening bleeding The net clinical benefit should be considered in light of their prothrombotic potential (~ 1.4% for PCC; up to 10% with rFVIIa) Specific reversal agents are in development Dentali F. Thromb Haemost. 2011 Sep;106(3):429-38. PMID: 21800002. Levi M. N Engl J Med. 2010 Nov 4;363(19):1791-800. PMID: 21047223. Seigal DM, Cuker A. Drug Discov Today 2014. [Epub ahead of print] PMID: 24880102. Management of Severe Bleeding: TSOACs Kaatz S. Am J Hematol. 2012 May;87 Suppl 1:S141-5. PMID: 22473649. Summary

TSOACs may provide a viable alternative to traditional anticoagulants in appropriately selected patients Optimal use of TSOACs requires familiarity with: Pharmacokinetic/ pharmacodynamic profiles Various dosing strategies Laboratory measurement Peri-procedural strategies Switching strategies General approaches to bleed management Familiarity with reversal strategies Thank you

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