New Oral Anticoagulants (NOACs) Dabigatran (Pradaxa) Rivaroxaban (Xarelto)

Apixaban (Eliquis) Edoxaban (Savaysa)

Janice Lawson, MD Tallahassee Memorial Hospital

Cancer and Hematology Specialists

Disclosure

No financial conflicts of interest

Brief discussion regarding off-label use of PCCs for anticoagulant reversal

Goals of discussion

• How do the NOAC’s work – Important considerations

• FDA-approved indications • Peri-procedural management • Subpopulation considerations

FDA approval

Warfarin

Heparin

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Leung The Hematologist 2011

Why do the NOACs seem better than warfarin?

Weitz. Hematology 2012. 536-540

Parameter Dabigatran (Pradaxa)

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Target Thrombin Factor Xa Factor Xa

Dosing Fixed, once or twice daily (can’t crush)

Fixed, once or twice daily (with food)

Fixed, twice daily

Prodrug? Yes No No

Half-life (hr) 7-17 (wide variability) 7-13 6-14

Peak Conc (hr) 1-3 2-4 1-3

Renal/Biliary Cl 80%/20% 66%/33% 25%/75%

Potential Drug Interactions

Potent P-gp inhibitors Potent CYP3A4 and P-gp inhibitors

Potent CYP3A4 and P-gp inhibitors

Dose adjustments (afib)

CrCl 15-30: 75mg BID; CrCl<15: CI Severe hepatic dz: CI

CrCl 15-50:15mg QD CrCl<15: CI Severe hepatic dz: CI

Any 2 (>80yo, <60kg, Cr>1.5) or CrCl 15-24: 2.5 BID. Sev hepatic dz: CI

Safe in Pregnancy? No No No

Antidote? No No No

Monitoring? PTT, thrombin time Anti-Xa level, ?PT Anti-Xa level TRIALS EXCLUDED PATIENTS WITH CRCl of less than 25-30ml/min

Drug-drug interactions • NOACs are substrates for CYP3A4 and/or P-glycoprotein enzymes

• Strong dual inducers: Reduce effect – Rifampin, carbamazepine, phenytoin, phenobarbital, St. John’s wort

• Strong dual inhibitors: Increase effect – ketoconazole/itraconzaole, HIV protease inhibitors,

• Strong P-gp inhibitors: Increase effect – Amiodarone, dronedarone (multaq), verapamil, quinidine

Rivaroxaban Apixaban Edoxaban Dabigatran Interactions 3A4/P-gp 3A4/P-gp P-gp P-gp

NOACs & “Reversal” • No true reversal agents for new oral anticoagulants

– Three main antidotes for NOACs are being investigated

• FFP, cryoprecipitate, platelets, protamine NOT generally useful – Despite the fact that standard coagulation studies (PT/PTT) may be

prolonged

• Prothrombin complex concentrates (PCCs – Profilnine; Kcentra)

and/or recombinant VIIa (Novoseven) may be useful – Doesn’t reverse/NOT an antidote. NOT 100% reliable. – May help generate thrombin (HIGH concentration of factors) – Risk of thrombosis (main side effect) in an already high-risk population – To be used ONLY in life-threatening bleeding/emergent surgery

Patient Concerns: Bleeding

• Lack of reversal agents/antidotes may make some patients reluctant to use NOACs

• Life-threatening/fatal bleeding are reduced by up to 50% for NOACs vs warfarin

• Outcomes with NOAC-associated major bleeding are no worse than with warfarin

Yang. Vasc Health Risk Manag. 2014 Sarode, et al. Circulation. 2013 Majeed, et al. Thromb Haemost Medscape Education

FDA-APPROVED INDICATIONS

Atrial fibrillation VTE prophylaxis after THA/TKA VTE treatment and secondary prophylaxis

Atrial fibrillation trials

Trial Patients/ Mean CHADS2

Drug Comparator Primary Efficacy Outcome (CVA)

Primary Safety Outcome (major bleeding)

RELY 18,000/ 2.1

Dabigatran 110mg BID or 150mg BID

Warfarin 110: Noninf 150: Superior

110: less 150: same

ARISTOTLE 18,000/ 2.1

Apixaban 5mg BID*

Warfarin

Superior Less

ENGAGE AF 21,000/ 2.8

Edoxaban 30mg QD or 60mg QD

Warfarin *Both: Noninf

Less (30mg: less GI)

ROCKET 14,000/ 3.5

Rivaroxaban 20mg QD

Warfarin Noninferior Same

Connolly NEJM 2009 Patel NEJM 2011 Connolly NEJM 2011 Granger NEJM 2011

* boxed warning for patients with CrCl > 95ml/in

Dosing strategies Trial Dosing Strategies

(vs dose-adjusted warfarin to target INR 2.0-3.0)

RELY (Dabigatran)

Dabigatran 110mg BID (low) or 150mg BID (high)

ROCKET AF (Rivaroxaban)

Rivaroxaban 20mg QD Dose adjustment 15mg daily for CrCl of 30-49 ml/min

ARISTOTLE (Apixaban)

Apixaban 5mg BID Dose adjustment 2.5mg BID if 2 or more factors present 1) Age >/= 80, Body weight </= 60kg, SCr >/= 1.5 mg/dL

ENGAGE AF (Edoxaban)

Edoxaban 60mg QD (low) or 30 mg QD (high) Dose adjustment halved if 1 of the factor CrCl 30-50 ml/min, Body weight </= 60kg; OR concomitant use of p-GP inhibitor verapamil, quinidine, and dronedarone

Connolly NEJM 2009 Patel NEJM 2011 Granger NEJM 2011 Giugliano NEJM 2013

One size does NOT fit all!

THA/TKA VTE prophylaxis trials

• Primary Efficacy Outcome: Total VTE and death

– Prophylactic rivaroxaban (10mg qday, 6-8 hrs post-op) superior – Pooled analysis: Non-significant trend towards increased

bleeding although still low – Biased reporting of adverse events – Could LMWH still be more appealing than rivaroxaban?

Erikkson Annu Rev Med 2011

VTE trials Trials Patient Drug Comparator Efficacy

Outcome (recurrent VTE)

Safety Outcome (major bleeding)

EINSTEIN-DVT/PE

3,500 / 4,800

Rivaroxaban 15mg BID x 3wks 20mg QD x 12mo

Enoxaparin warfarin 12mo

Non-inferior Same/Better

RECOVER 2,500 Parenteral x 9d Dabigatran 150mg BID x 6mos

Parenteral warfarin 6mo

Non-inferior Same

AMPLIFY 5,300

Apixaban 10mg BID x 1 wk 5mg BID x 6 mo

Enoxaparinwarfarin 6 mo

Non-inferior Better

HOKUSAI-VTE

8,300 Parenteral x 5-10d Edoxaban 60mg (30mg*) QD x 3-12 mo

Parenteral warfarin 6mo

Non-inferior Same/Better

EINSTEIN Inv, NEJM 2010 Schulman, NEJM 2009 Agnelli, NEJM 2013 Hokusai Inv NEJM 2013 * CrCl 30-50ml/min, wt<60kg

PERI-PROCEDURAL CONSIDERATIONS

Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis)

Peri-procedural considerations

• Balance risks of bleeding vs risks of clotting – Patients at the highest risk of peri-procedural bleeding tend

to also have an increased risk of thrombosis (elderly, active cancer)

• Evidence to support peri-procedural recs is weak – observational data, subset review of trial patients, and

consensus documents/expert opinions • Short half-life of NOACs may be an advantage

– Rapid interruption and reintroduction – Likely no need for standard peri-procedure heparin

bridging

Fawole, et al. Cleve Clin J Med. 2013; 80(7): 443-51

Lab assessment

Dabigatran (Pradaxa)

Rivaroxaban (Xarelto)

Apixiban (Eliquis)

PT

Less useful (higher Rx conc)

May be useful (variably sensitive)

Not useful

aPTT Useful (less sensitive)

Not useful Not useful

Thrombin time Useful Not useful Not useful

Anti-Xa assay Not useful Useful Useful • Labs may be useful for qualitative assessment, but not for

quantitative use (ie. not for monitoring levels)

Garcia. J of Thromb and Haem. 2012; 11: 245-252 Fawole, et al. Cleve Clin J Med. 2013; 80 (7): 443-451

How about restarting?

Connolly. J Thromb Thrombolysis. 2013; 36: 212-222

• For patients at high risk for thromboembolism, consider administering a reduced dose of NOAC on the evening after surgery and on POD #1:

Dabigatran, 75mg qday; Rivaroxaban, 10mg qday; or Apixiban 2.5mg bid

• In general, no need for post-operative heparin or LMWH bridging, unless patient’s status precludes taking oral medications or if there are concerns about absorption.

Elderly Antiplatelet therapy Cancer patients

SUBPOPULATIONS

Elderly

• Patients in clinical trials have been younger than those in practice – RELY (dabi): 40% age >/= 75 – ROCKET (riva): 25% age >/= 78

– But how many of our patients are >/= 80?

• Intrinsic factors that increase their risk of bleeding

– Falls – Low body weight (</= 60 kg) – Comorbidities (renal impairment, hepatic dysfunction, malignancy,

less buffering capacity in the GI tract, capillary fragility) – Need to follow more closely

Schulman Thrombosis Research 2013 Maddula J Thromb Thrombolysis 2013

Age and Efficacy/Safety

Schulman Thrombosis Research 2013 Eikelboom Circulation 2011

Antiplatelet therapy Role of “Triple Therapy:” • Atrial fibrillation with concomitant CAD requiring PCI is present in 20-30% of patients with atrial fibrillation • Requirement of dual antiplatelet regimen (ASA + ADP inhibitor – clopidogrel - to prevent in-stent thrombosis) in addition to anticoagulation for CVA prevention

Data is Limited: •Aspirin (<100mg/d):

–RE-LY (Dabi) 20%, ROCKET (Riva) 35%, ARISTOTLE (Apixa) 30%

•Patients on dual antiplatelet therapy were excluded from ROCKET (Riva) and ARISTOTLE (Apixa)

Huber, Am Heart J 2014; Schulman ,Thrombosis Research 2013; Furie, Stroke 2012

Triple Therapy Data from ACS patients •ATLAS ACS2-TIMI 51 – Rivaroxaban (2.5mg or 5mg bid) + standard medical therapy (ASA +/- thienopyridine)

– Both doses increased the rates of major bleeding and ICH

•APPRAISE2 – Apixaban + ASA +/- thienopyridine for ACS. – Stopped early due to increased major bleeding and no significant

reduction in recurrent ischemic events.

•PIONEER AF-PCI Trial - Rivaroxaban + DAPT vs Warfarin + DAPT ( d/c of thienopyridine) vs Rivaroxaban + clopidogrel (Rivaroxaban doses: 2.5 mg bid, 10/15mg qday)

Huber, Am Heart J 2014; ClinicalTrials.gov: NCT01830543

Cancer Patients • Up to 20% of all cancer patients (2nd leading cause of death) • NOACs appeared at least as effective as warfarin

• Some points to remember:

– Approx 5% or less of patients enrolled in NOAC trials had cancer – Comparison arm warfarin, not LMWH (standard of care) – Concern about drug-drug interactions (biologics) – Chemotherapy related GI toxicities (compliance and absorption) – None of the trials were dedicated VTE in cancer trials

• Rivaroxaban vs dalteparin (Select-d trial) • Edoxaban vs dalteparin

Current opinion: Insufficient data to support NOACs in the upfront management of VTE in cancer patients.

Efficacious Safe Convenient

What DO we know?

What DON’T we know? • Effective in real world settings?

– 20% non-adherence negative impact on efficacy? - Cost

• Long term data? – Short term follow-up in clinical trials (~2 years) vs 50 years for

warfarin

• Is lack of monitoring a good thing?

– Lost opportunity for repetitive patient education? – Prescribe-and-forget drug? – Average time spent educating patient on rationale, efficacy, and safety

of new med is < 1 minute*

* Tarn Patient Educ Counsel 2008.