The Blood Thins and the Plot Thickens American College of Physicians Annual Scientific Meeting November 7, 2014 Allison Burnett, PharmD, CACP, PhC Clinical

Overview of Target-Specific Oral Anticoagulants (TSOACs)

The Blood Thins and the Plot Thickens

American College of Physicians Annual Scientific MeetingNovember 7, 2014

Allison Burnett, PharmD, CACP, PhCClinical Assistant Professor- UNM College of RxTeam Lead- Inpatient Anticoagulation Services

University of New Mexico Hospital

• Anticoagulation Forum • Board member• Honoraria

• Society of Hospital Medicine (SHM)• Honoraria

• Island Peer Review Organization (IPRO)• Honoraria

Disclosures

Appropriate patient selection

Laboratory measurement

Peri-procedural management

Switching between agents

Management of severe bleeding

Practical Management of TSOACs







Which of the following patients would be considered a good candidate for TSOAC therapy?

A. 64-year-old male with a St. Jude’s 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

Case 1

TSOAC: Mechanism of Action

Adapted from Weitz JI, Bates SM. J Thromb Haemost 2005; 3: 1843-53.

Agent EU US Canada Japan

Rivaroxaban(Xarelto®)

NVAF VTE PPX VTE TX

ACS

NVAFVTE PPX VTE TX

NVAF VTE PPX VTE TX

Apixaban(Eliquis®)

NVAF VTE PPX

NVAFVTE PPXVTE TX

NVAF VTE PPX

Dabigatran(Pradaxa®)

NVAFVTE PPXVTE TX

NVAF

VTE TX

NVAF VTE PPX

Edoxaban(Lixiana®) VTE PPX

TSOACs: Approved Indications Siegal DM

, et al. J Thromb Throm

bolysis 2013; 35: 391-98.

ACS = acute coronary syndrome; NVAF = non-valvular atrial fibrillation; PPX = prophylaxis; TX = treatment; VTE = venous thromboembolism

Comparison of Oral Anticoagulants

Cove CL, Hylek EM. J Am Heart Assoc. 2013; 2:e000136.

Agent Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban

Target IIa, VIIa, IXa, Xa IIa Xa Xa Xa

Peak effect 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

Antidote Vitamin K No No No No

Lab measure INR aPTT (qual) PT (qual) No data PT (qual)

P-gp = p glycoprotein3A4 = cytochrome P450 3A4qual = qualitative

• 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

TSOACs: Advantages

Bauer KA. ASH Education Book 2013; 1:464-470Ruff CT, et al. Lancet 2013; 383 (9921): 955-62

• 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)

TSOACs: Disadvantages

Bauer KA. ASH Education Book 2013; 1:464-470Majeed A, et al. Circulation 2013; 128)21): 2325-32

• Varies by:–TSOAC – Indication–Country

• May require adjustment for:–Renal impairment–Age–Weight–Drug interactions–A combination of the above

TSOAC: Dosing

Apixaban Dabigatran Rivaroxaban

Non-valvular atrial fibrillation

5 mg PO BID2.5 mg PO BID*

150 mg PO BID75 mg PO BID*

CrCl <15 mL/minAvoid use

20 mg PO daily15 mg PO daily*


VTE prophylaxis(orthopedic)

2.5 mg PO BID


N/A 10 mg PO daily


VTE treatment and prevention of recurrence

N/A 150 mg PO BID after 5-10 days of parenteral anticoagulation


15 mg PO BID x 21 days, then 20 mg PO daily


TSOACs: Dosing (FDA Labeling)

* 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

• 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

Appropriate Patient Selection

Ageno W, et al. J Thromb Haemost 2013; 11: 177-9.







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)

Case 2

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.

• 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


Test Dabigatran Rivaroxaban Apixaban

aPTT* ↑↑ ↑ ↑/ no effect

PT* ↑ ↑↑ ↑/ no effect

TT ↑↑↑ No effect No effect

ECT ↑↑ No effect No effect

Anti-Xa** No effect ↑↑ ↑↑

*Variability by reagent/instrumentation**Drug-specificTT = thrombin timeECT = ecarin clotting time

Effect of TSOAC on Coagulation Assays

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.


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)

Measurement of TSOACs“Rules of Thumb”







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 peri-procedural anticoagulation?

A. Do not interrupt TSOAC therapy for this procedureB. Hold TSOAC for 2-3 half-lives prior to this low bleed risk procedureC. Hold TSOAC for 4-5 half-lives prior to this high bleed risk procedureD. Hold TSOAC for 5 days prior to procedure and use LMWH as bridging therapy

Case 3

~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:◦ Patient’s renal function◦Half-life of TSOAC◦ Type of procedure and anesthesia

Peri-Procedural Management: TSOACs

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.

Risk Assessment

High Bleed Risk Low Bleed Risk Minimal Bleed Risk

High thromboembolic

risk

Interrupt TSOAC

Consider interrupting

TSOAC Do not interrupt TSOAC

Moderate thromboembolic

risk

Low thromboembolic

risk

Interrupt TSOAC

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/

http://qio.ipro.org/drug-safety/drug-safety-resources

http://excellence.acforum.org/

Cessation of TSOAC◦Dependent on patient’s 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.

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



• 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

Peri-Procedural Challenges








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 multi-vessel 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 indefinitelyB. Stop dabigatran. Overlap LMWH and warfarin until INR >2, along with antiplatelet therapyD. Stop anticoagulation and continue only dual antiplatelet therapy

Case 4

• 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

Switching Between Anticoagulants

Abo-Salem E, et al. J Thromb Thrombolysis 2014; 37: 372-79.

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 patient’s coagulation

status◦ Patient’s renal function


Abo-Salem E, et al. J Thromb Thrombolysis 2014; 37: 372-79.

• 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 Betw

een Anticoagulants







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 apixabanB. Oral activated charcoal to remove the apixabanC. Concentrated factors (PCC, aPCC, rFVIIa) to reverse apixabanD. Supportive care and investigate for source of the bleed

Case 5

• 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

Management of Severe Bleeding: TSOACs

Hierarchy of Evidence: Reversal of TSOACs Seigal DM

, Cuker A. Drug D

iscov Today 2014. [Epub ahead of print] PMID

: 24880102.

• 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

Concentrated Factors for TSOAC Reversal

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.

• 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

Summary

Thank you

Documents

The Blood Thins and the Plot Thickens American College of Physicians Annual Scientific Meeting November 7, 2014 Allison Burnett, PharmD, CACP, PhC Clinical