Noval Oral Anticoagulants:Life Is Not As Simple as AnticipatedPRESENTED BY

VICKI L GROO, PHARMD

CLINICAL ASSOCIATE PROFESSOR

DEPARTMENTS OF PHARMACY PRACTICE AND CARDIOLOGY

UNIVERSITY OF ILLINOIS AT CHICAGO

Provider

Patient

NOACs DOACs

Objectives: Review dosing for atrial fibrillation and venous thromboembolism

Provide guidance on when to hold NOACs for procedures

Review options for reversal

Discuss what is on the horizon for new indications and dosing

NOAC Dosing

NOAC Dosing

Renal Impairment: ◦ Afib: Renal or patient characteristic dose adjustments Some based on PK modeling only (ie no clinical data)

◦ VTE: varies by drug, check prescribing guide Contraindicated for CrCl < 30 ml/min vs renal dose adjustment vs no adjustment

Drug interactions◦ PgP inhibitors: Increase exposure (dabigatran and edoxaban)

◦ Strong CYP3A4 + PgP inhibitors: Increase exposure (apixaban and rivaroxaban)

◦ PgP inducers or PgP + CYP3A4 inducers: Decrease exposure CONTRAINDICATED ALL

VTE initial treatment varies◦ Duration

◦ LMWH vs oral “load”

NOAC Dosing: Apixaban (Eliquis)

No Dose adjustments on CrCl alone Non-valvular Afib DVT/PE

Most patients 5 mg bid ---------------------

When 2 characteristics presentAge ≥ 80; Wt ≤ 60 kg; SrCr ≥ 1.5 2.5 mg bid ---------------------

ESRD on HDIf Age ≥ 80 OR Wt ≤ 60 kg

5 mg bid*2.5 mg bid* ---------------------

Initial Dose --------------------- 10 mg bid x 7 days*

Maintenance Dose --------------------- 5 mg bid*

Extended Rx to prevent recurrence --------------------- 2.5 mg bid*

XA inhibitor with combined renal (30%) and liver eliminationStart when INR < 2.0 if switching from warfarinUse parenteral agent until INR therapeutic if switching to warfarin

https://packageinserts.bms.com/pi/pi_eliquis.pdf

* Based on PK modeling for ESRD on HD

NOAC Dosing: Dabigatran (Pradaxa)

Store original bottle / swallow whole Non-Valvular Afib DVT/PE^

CrCl > 30 ml/min 150 mg bid 150 mg bidMaintenance dose and toreduce risk of recurrence

CrCl 15-30 ml/min 75 mg bid * contraindicated

CrCl < 15 ml/min contraindicated contraindicated

Direct thrombin inhibitor with 80% renal elimination DialyzableStart when INR < 2.0 if switching from warfarinIf switching to warfarin, overlap with warfarin as follows:CrCl > 50 x 3 days / Cr Cl 31-50 x 2 days / Cr Cl 15-30 x 1 day

^ Treat 1st with LMWH or UFH x 5-10 days* Based on PK modeling for CrCl 15-30

http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf

NOAC Dosing: Edoxaban (Savaysa)

Non-Valvular Afib DVT/PE^

CrCl > 95 ml/min Contraindicated 60 mg daily

CrCl > 50 - ≤ 95 ml/min 60 mg daily 60 mg daily

CrCl 15-50 ml/min 30 mg daily* 30 mg daily*

CrCl < 15 ml/min contraindicated contraindicated

Any CrCl with weight ≤ 60 kg ------------------ 30 mg daily

http://dsi.com/prescribing-information-portlet/getPIContent?productName=Savaysa&inline=true

^ Treat 1st with LMWH or UFH x 5-10 days* Based on PK modeling for CrCl 15-30

XA inhibitor with 50% renal eliminationStart when INR < 2.5 if switching from warfarinIf switching to warfarin;reduce dose by 50% then d/c when INR therapeutic or Use parenteral agent until INR therapeutic

NOAC Dosing: Rivaroxaban (Xarelto)

Take with food (usually pm meal) Non-valvular Afib DVT/PE

Initial Dose ---------------------- 15 mg bid x 21 days

Maintenance Dose 20 mg daily 20 mg daily

CrCl < 50 ml/min including ESRD on HD 15 mg daily* ----------------------

Extended Rx to prevent recurrence ---------------------- 20 mg daily

Contraindicated ---------------------- CrCl < 30 ml/min

https://www.xarelto-us.com/shared/product/xarelto/prescribing-information.pdf

* Based on PK modeling for CrCl 15-30 or ESRD on HD

XA inhibitor with combined renal (66%) and liver eliminationStart when INR < 3.0 if switching from warfarinUse parenteral agent until INR therapeutic if switching to warfarin

NOAC Dosing: The need to get it right

NOAC dosing patterns and associated outcomes in patients with Afib and renal impairment

14,865 patients from Optum Data Warehouse (Medicare Advantage enrollees) ◦ Started apixaban, dabigatran or rivaroxaban from 10/1/2010 to 9/30/2015

◦ Creatinine available before treatment initiation

Outcomes: Ischemic stroke or systemic embolism and major bleeding

eGFR calculated using CKD-EPI (Sr Cr, age, gender, race)◦ Apixaban if SrCr > 1.5 (sensitivity analysis performed for age > 80)

Propensity score matching used to balance baseline characteristics b/t reduced and standard dose patients

Yao X, Shah ND, Sangaralingham LR, et al. J Am Coll Cardiol 2017;69:2779-90

NOAC Dosing: The need to get it right

1473 with indication for dose reduction

79 years GFR 39, CHADSVASc =5 HAS-BLED= 4

13,392 no indication for dose reduction

70 years, GFR 73 CHADSVASc = 4 HAS-BLED = 2

43% received standard doseOVERDOSE

13.3 % received reduced doseUNDERDOSED

Stroke/ 100 pt yrs2.32S vs 1.85R

P=0.48

Bleed/ 100 pt yrs11.29S vs 5.06R

P=0.03

Stroke/ 100 pt yrs1.43S vs 1.70R

P=NS

Bleed/ 100 pt yrs5.03S vs 5.43R

P=NS

Apixaban 5x risk of

stroke

Yao X, Shah ND, Sangaralingham LR, et al. J Am Coll Cardiol 2017;69:2779-90, Nielsen PB, Skjoth F, Sogaard M, et al. BMJ 2017;356 doi: https://doi.org/10.1136/bmj.j510

Surgical Interruption

Surgical Interruption:Estimate thromboembolic risk: Applies to evaluation need for bridging

Risk Stratum A Fib VTE

Very High CHADSVASC score ≥ 6CVA or TIA within 3 monthsRheumatic valvular disease

VTE within 3 monthsSevere thrombophilia*

High CHADSVASC score of 4-5 VTE in past 3-12 monthsNon-severe thrombophilia^Recurrent VTEActive cancer

Moderate CHADSVASC score of 2-3 VTE > 12 months and not other risk factors

Douketis JD, Spyropoulos AC, Spencer FA, et al. Chest 2012; 141(2 Suppl):e326S, Doherty JU, Gluckman TJ, Hucker WJ, et al. J Am Coll Cardiol 2017;69:871-898

* Protein C or S deficiency, antithrombin or antiphospholipid antibodies^ heterozygous factor V Leidein or prothrombin gene mutation

Bridging is NOT

recommended during

therapeutic interruption for NOACs

Surgical InterruptionPATIENT BLEED RISK FACTORS

HAS-BLED parameters ◦ Hypertension

◦ SPB > 160mmHg

◦ Abnormal renal function ◦ dialysis/transplant or Cr > 2.6

◦ Abnormal liver function ◦ (cirrhosis, ALT/AST > 3x ULN or bili > 2x ULN)

◦ Prior Stroke◦ Bleeding

◦ Hx of anemia or predisposition

◦ Labile INR (VKA)◦ Elderly

◦ > 65 years

◦ Antiplatelet or NSAID use◦ Drug or alcohol use

◦ > 8 drinks/week

Other◦ ICH or other bleed in last 3 months◦ Bleed history with similar procedure◦ Quantitative or qualitative platelet abnormality

◦ uremia

◦ Bleed history from previous bridging

HAS-BLED Scoring 1 point each

Score ≥ 3 predictive of bleeding events during bridging

Doherty JU, Gluckman TJ, Hucker WJ, et al. J Am Coll Cardiol 2017;69:871-898Omran H, Bauersachs R, Rubenacker S, et al. Thromb Haemost 2012;108:65-73

Surgical Interruption: Surgical Risk EvaluationMinimal Bleeding Risk Low Bleeding Risk

2 day risk of major bleed < 2%High Bleeding Risk 2 day risk of major bleed ≥ 2%

Minor dermatologic procedures(e.g. excision of basal and squamous skin cancers, actinic keratosis, and premalignant or cancerous skin nevi)

Cataract proceduresDental cleanings, fillings

Minor dental procedures (simple dental extractions, restorations, prosthetics, endotonics)

Cutaneous/lymph node biopsiesShoulder/foot/hand surgeryCoronary angiographyEP procedures: ICD implant/ ablationsGI scope +/- biopsyAbdominal hysterectomyHemorrhoidal surgeryBronchoscopy +/- biopsyEpidural injections with INR < 1.2Pacemaker battery changeArthroscopy

Cancer surgeryMajor orthopedic surgeryReconstructive plastic surgeryTURP, blader resection or tumor ablationNephrectomy, kidney biopsyColonic polyp resectionBowel resectionPEG placement or ERCPCardiac, intracranial, or spinal surgerySurgery in high vascular organsAny major operation > 45 min

Doherty JU, Gluckman TJ, Hucker WJ, et al. J Am Coll Cardiol 2017;69:871-898—Online Appendix for complete list

Surgical Interruption

UIC guide is up to 3 days

Doherty JU, Gluckman TJ, Hucker WJ, et al. J Am Coll Cardiol 2017;69:871-898

Check Creatinine Clearance!!!

Surgical Interruption

Resume NOAC

1 day after low bleeding risk procedures

2-3 days after high bleeding risk procedures

AND

Adequate hemostasis is achieved

Surgical Interruption: Other Considerations

Post procedural VTE prophylaxis with AC not needed: Patient is fully anticoagulated◦ Can still consider pneumatic compression if appropriate

◦ Can consider prophylactic doses of NOAC, LMWH, or UFH 6-8 hours post procedure until appropriate to increase to full treatment dose.◦ Apixaban 2.5 mg bid

◦ Dabigatran 150 mg daily

◦ Edoxaban 15-30 mg daily

◦ Rivaroxaban 10 mg daily

Neuraxial Anesthesia◦ All have black box warning risk of spinal or epidural hematoma

◦ Each PI provides guidance

◦ American Society of Regional Anesthesia and Pain Management wait 24 hours after catheter removal

Doherty JU, Gluckman TJ, Hucker WJ, et al. J Am Coll Cardiol 2017;69:871-898Narouze S, Benzon HT, Provenzano DA, et al. Reg Anesth Pain Med 2015;40:182-212

Surgical Interruption

Doherty JU, Gluckman TJ, Hucker WJ, et al. J Am Coll Cardiol 2017;69:871-898

Reversal

Reversal No reversal agents available during landmark clinical trials

Management and Outcomes of Major Bleeding: Dabigatran vs Warfarin◦ 27,419 patients treated for 6-36 months in 5 phase III trials

◦ 1034 patients (627 dabigatran and 407 warfarin) had 1121 major bleeds

◦ Dabigatran patients were older, had lower CrCl, and more often used aspirin or NSAIDS

◦ 30 day mortality favors dabigatran (9.1% vs 13%, p=0.057) ◦ OR after adjustment 0.66 ( p=0.051)

◦ ICU stay favors dabigatran (1.6 vs 2.7 nights, p = 0.01)

◦ Dabigatran more likely to receive blood transfusion / warfarin received plasma

Who should reversal be considered in?◦ Emergent need for surgery or invasive procedure (4-6 hours) and/or

◦ Major bleeding while on antithrombotic therapy

Majeed A, Hwang HG, Connoly SF, et al. Circulation 2013;128:2325-32

NOAC Reversal Agents

Agent Idarucizumab Andexanet Alfa Ciraparantag

Target Dabigatran only Factor Xa inhibitors* UFH, Factor XA inhibitors, Dabigatran

Mechanism Humanized antibody fragment;

binds dabigatran with 350x the

affinity of thrombin

Recombinant modified human factor Xa

decoy protein; directly binds target and

restores activity of factor Xa

Small synthetic molecule; directly binds drug

target to block binding to target site

Onset < 10 minutes 2 – 5 minutes 5 – 20 minutes

FDA Approval FDA 2015 Currently delayed by FDA until more data

with edoxaban and enoxaparin

FDA granted fast track review in April 2015

Currently in Phase 3 studies

Administration 5 gm total given as 2 consecutive IV

bolus or infusion (2.5 gm each)

Dose based on drug and timing of last

dose; IV bolus + 2 hour infusion

IV bolus; future studies may include infusion

Data 90 pts (ICH, GI, trauma) / procedure

clotting times normalized 88-98%

33/36 normal procedure hemostasis

11.4 hrs to hemostasis in bleeds

Healthy subjects: AntiXA activity ↓92-94%

ANNEXA 4 ongoing:

67 pts bleeding (GI and ICH)

Excellent/good hemostasis 79%

Healthy volunteer studies with edoxaban and

enoxaparin; reverses effect on whole blood

clotting time

https://www.praxbind.com. Pollack CV, Reilly PA, Eikelboom J, et al. N Engl J Med 2015;373:511-20. Siegal DM Curnutte JT, Connolly SJ, et al. N Engl J Med 2015;373:2413-24. Connoly SJ, Milling TJ, Eikelboom JW, et al. N Engl J Med 2016;375:1131-1141,Milling TJ, Kaatz S. Am J Emerg Med 2016;34:39-45

NOAC Reversal Agents

Agent Idarucizumab Andexanet Alfa Ciraparantag

Target Dabigatran only Factor Xa inhibitors* UFH, Factor XA inhibitors, Dabigatran

Mechanism Humanized antibody fragment;

binds dabigatran with 350x the

affinity of thrombin

Recombinant modified human factor Xa

decoy protein; directly binds target and

restores activity of factor Xa

Small synthetic molecule; directly binds drug

target to block binding to target site

Onset < 10 minutes 2 – 5 minutes 5 – 20 minutes

FDA Approval FDA 2015 Currently delayed by FDA until more data

with edoxaban and enoxaparin

FDA granted fast track review in April 2015

Currently in Phase 3 studies

Administration 5 gm total given as 2 consecutive IV

bolus or infusion (2.5 gm each)

Dose based on drug and timing of last

dose; IV bolus + 2 hour infusion

IV bolus; future studies may include infusion

Data 51 bleeding pts (ICH, GI, trauma)

39 urgent procedures

clotting times normalized 88-98%

33/36 normal procedure hemostasis

11.4 hrs to hemostasis in bleeds

Healthy subjects: AntiXA activity ↓92-94%

ANNEXA 4 ongoing: 67 pts reported

Excellent/good hemostasis 79%

Healthy volunteer studies with edoxaban and

enoxaparin; reverses effect on whole blood

clotting time

https://www.praxbind.com. Pollack CV, Reilly PA, Eikelboom J, et al. N Engl J Med 2015;373:511-20. Siegal DM Curnutte JT, Connolly SJ, et al. N Engl J Med 2015;373:2413-24. Connoly SJ, Milling TJ, Eikelboom JW, et al. N Engl J Med 2016;375:1131-1141,Milling TJ, Kaatz S. Am J Emerg Med 2016;34:39-45

NOAC Reversal: PCCs

Use for XA inhibitors

3-factor PCC: (II, IX, X) 50 U/kg IV, may repeat q 12 hours

4-factor PCC: (II, VII IX, X, Protein C and S) 50 U/kg x 1◦ FEIBA® has activated factor VII ? Thromboembolic risk

◦ KCentra® all inactivated factors

◦ Dose not based on INR!!!

What do we know?◦ Animal models of bleeding; decreased blood loss

◦ Healthy subjects; reverses abnormal coagulation values, decreases bleeding, improves hemostasis

◦ ICH; 18 pts suggested reduces hemorrhagic complications and hematoma expansion

Eikelboom , Merli G. Am J Emerg Med 2016;34:3-8, Nutescu EA, Dager WE, Kalus JS, et al. Am J Health-Syst Pharm 2013;70:e82-97

NOAC Reversal Summary

Major Bleeding or

Urgent invasive procedure

XA Inhibitor

PCC

Dabigatran

Idarucizumab

Other Considerations:• Time of last dose and half-life of drug

• Dabigatran 12-14 hours, increases with declining renal fxn

• Apixaban 8-15 hours• Edoxaban 10-14 hours• Rivaroxaban 5-9 hours, increases to

11-13 hours in elderly

• Activated charcoal for overdose • Dialysis for dabigatran

Prevent Bleeding

Patient selectionCorrect DoseAntiplatelet

NSAIDs

What’s New

COMPASS

27,395 patients with stable ASCVD◦ Rivaroxaban 2.5 mg bid + ASA 100 mg daily

◦ Rivaroxaban 5 mg bid + placebo

◦ ASA 100 mg daily + placebo

Primary outcome: CV death, stroke or MI

Key Inclusion/Exclusion◦ Age < 65 had to have ASCVD in 2 vascular beds or 2 additional risk factors (smoking, DM, eGFR < 60 mL/min, heart

failure, nonlacunar ischemic stroke > 1 month

◦ eGFR < 15 mL/min, severe HF, high bleeding risk, DAPT, anticoagulation

Population: 68 years, male, 62% white on ACEi or ARB, beta-blocker and lipid lowering agent

Outcomes: rivaroxaban 2.5 mg bid + ASA (4.9%) vs ASA (5.4%) HR 0.76, p<0.001◦ Increased risk of major bleeding with combination: 3.1 vs 1.9%, HR 1.70, p>0.001

◦ Net clinical benefit (1○ outcome + fatal/critical organ bleeding) favors combination: 4.7 vs 5.9%, HR 0.8, p<0.001

Eikelboom JW, Connolly SJ, Bosch J, et al. N Engl J Med 2017;377:1319-1330

PIONEER2124 patients with atrial fibrillation in need of PCI with stent

◦ Rivaroxaban 15 mg once daily (10 mg if CrCl 30-50 mL/min) + P2Y12 inhibitor x 12 months

◦ Rivaroxaban 2.5 mg bid + DAPT x 1, 6, or 12 months◦ After 1 or 6 months of triple therapy completed, dose change to 10-15 mg daily + ASA until 12 months

◦ Dose adjusted VKA + DAPT x 1, 6, or 12 months

◦ Duration of DAPT specified by investigator prior to randomization

Primary outcome: clinical significant bleeding

Key exclusion:◦ CrCl < 30 ml/min, Hx of CVA/TIA or GI bleed in last 12 months, Hgb < 10 g/dL

Population: 70 years, white, CrCL 77-80 mL/min (28% < 60 mL/min), clopidogrel, DES 66%

Outcomes: ◦ Both rivaroxaban groups had lower rates of bleeding than warfarin (HR 0.59 and 0.63, p<0.001)

◦ No difference in MACE (HR 1.08, p 0.75 and HR 0.93, p 0.76)

Gibson CM, Mehran R, Bode C, et al. N Engl J Med 2016;375:2423-34

EINSTEIN CHOICE3365 patients with VTE randomized after 6-12 months of treatment

◦ Rivaroxaban 20 mg daily

◦ Rivaroxaban 10 mg daily

◦ ASA 100 mg daily

Primary outcome: symptomatic recurrent VTE

Key Inclusion/Exclusion◦ Initial treatment could have been any AC, no more than 7 days interruption prior to randomization

◦ CrCl < 30 mL/min or hepatic disease associated with coagulopathy

Population: 58 yo, 55% male, 60% provoked, 20% prior VTE

Outcomes: rivaroxaban 20 mg (1.5%), 10 mg (1.2%), ASA (4.4%); HR 0.34 and 0.26, p<0.001◦ Major bleeding: rivaroxaban 20 mg (0.5%), 10 mg (0.4%), ASA 0.3%); HR 1.64, p=0.50

Weitz, JI, Lensing AWA, Prins MH, et al. N Engl J Med 2017;376:1211-22

Final Thoughts: NOACS SIMPLE Dosing Dosing varies by indication Pay attention to renal function and drug interactions New indications or doses on the horizon (2.5 mg dose of rivaroxaban not currently available)

Surgical interruption Based on risk and drug half-life Parenteral bridging is not necessary

Bleeding Idaruzimab for dabigatran PCC for XA New agents on the horizon

Refer to prescribing guides as needed

Create institutional clinical care guidelines and reference documents