Paradigm Shift In Oral Anticoagulation –Non-Vitamin K Oral ... · 1. Cabral KP. Pharmacology of the new target-specific oral anticoagulants. J ThrombThrombolysis. 2013;36(2):133-140

Paradigm Shift In Oral Anticoagulation – Non-Vitamin K Oral

Anticoagulants(NOACs) -Mohammad Taha, MD

University of Kansas Medical center, Kansas city, KSAbebe Abebe, MD

University of Kansas Medical Center, Kansas city, KS

No personal or financial interest to declare

Conflict of Interest

• Presentation of a case• Introduction to oral anticoagulants• Basic Pharmacology of NOACs• Use of Coagulation assays in NOACs• Literature review on efficacy and safety of NOACs• Role of NOACS in current Practice guidelines • Practice pearls in selecting and dosing NOACS

Outline

• High risk medications • Knowledge needed for prescribing & managing

complications • Update of new anticoagulation guidelines incorporating

NOACs• Provide updates on NOACs

Relevance

§ A 71 year old white female with history of Hypertension, DM-Type –II and Osteoarthritis

§ Shortness of breath for the last three days§ Long range flight to Paris for a vacation a week ago. § Pleuritic right sided chest pain § No past history of blood clots or bleeding.

Case presentation

§ Complete blood counts , PT/INR & aPTT were normal § Renal and hepatic function/Transaminases– normal § Left leg US - completely occlusive acute popliteal vein

thrombus§ CT of chest –right segmental pulmonary artery filling

defect § Discussion of anticoagulation options – Want to

avoid frequent lab draws§ What will be the anticoagulation of choice?

Case presentation

Warfarin( Vitamin K antagonist)

Advantages

* Oral* Once daily dosing * Easy to reverse* No adjustment with low GFR* Affordable

Pitfalls

* Delayed onset of action * Major drug or food interaction* Unpredictable

pharmacokinetics* Need for lab monitoring* Narrow therapeutic window

Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165(10):1095-1106.

Ideal anticoagulant

§ Oral § Rapid onset of action§ No major drug or food

interaction§ Once daily dosing § Predictable

pharmacokinetics

§ No need for laboratory monitoring

§ Easy to reverse§ Wide therapeutic window§ No adjustment with low

GFR§ Affordable

Eikelboom JW, Weitz JI. New anticoagulants. Circulation. 2010;121(13):1523-1532.

§ Novel oral anticoagulants § Non – Vitamin K antagonist oral anticoagulants(NOACs)1

§ Target specific oral anticoagulants(TSOAs)1

§ Direct oral anticoagulants(DOACs)2

§ Oral direct Inhibitors (ODIs)3

NOACs

1. Cabral KP. Pharmacology of the new target-specific oral anticoagulants. J Thromb Thrombolysis. 2013;36(2):133-140. 2. Levy JH, Spyropoulos AC, Samama CM, et al. Direct oral anticoagulants: new drugs and new concepts. JACC Cardiovasc Interv.

2014;7(12):1333-1351. 3. Baglin T, Hillarp A, Tripodi A, et al. Measuring oral direct inhibitors (ODIs) of thrombin and factor Xa: A recommendation from the

Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2013.

Taha M, Abebe A, Wooldridge D. New options in anticoagulation: a hospitalist’s guide to non–vitamin K antagonist oral anticoagulants.Hospital Medicine Practice. 2015;3(9):1-34

Dabigatran ( Pradaxa®)

§ Prodrug – Dabigatran etexilate § Peak plasma concentration – 1-2 hours§ Half life – 12-17 hours § Low plasma protein binding§ Renal elimination -80%.§ Can not be crushed .

Direct Thrombin Inhibitors(DTIs)

Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate.Clin Pharmacokinet. 2008;47(5):285-295.

Rivaroxaban (Xarelto®)

§ Peak plasma concentration – 2-4 hours § Half life - 5-9 hours ; 11-13 hours in elderly § High plasma protein binding § Renal clearance – 66%§ Needs to be taken with food to improve absorption .

Direct Factor Xa Inhibitors

Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285-295

Apixaban(Eliquis®)

§ Peak plasma level – 1-3 hours § Half life – 8-15 hours § High plasma protein binding§ Renal clearance -25%



Edoxaban(Savaysa®, Lixiana®)

§ Peak plasma level – 1-2 hours § Half life – 10-14 hours § Intermediate plasma protein binding§ Renal clearance- 50%



Betrixaban(Bevyxxa®)

§ Peak plasma level: 3- 4 hours § Half life : 19 – 27 hours § Plasma protein binding: 60%( in Vitro)§ Excretion : Feces ~ 85%§ Renal excretion: 6-13%



Comparative pharmacology of non-vitamin K antagonist oral anticoagulantsAbbreviations: Tmax, time to reach peak concentration in plasma after oral dose; h, hours; CYP450, cytochrome 450; T1/2, terminal half-life of drug; PD T1/2, pharmacodynamic half-life.

Chan etal. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vascular Health and Risk Management 2015:11 343–351

20%

* Retrospective study - Taiwan National Health Insurance database* 91,330 patients with Nonvalvular A.fib( Dabigatran, Rivaroxaban

or Apixaban) * 4770 major bleeding occurred * Among patients taking NOACs for nonvalvular atrial fibrillation,

concurrent use of amiodarone, fluconazole, rifampin, and phenytoin compared with use of NOACs alone, was associated with increased risk of major bleeding.

* For example, the bleeding rate with amiodarone plus NOACs was 52 per 1000 person-years of exposure, versus 38 per 1000 with NOACs alone

Chang-Fu et al. JAMA October 3, 2017 Volume 318, Number 13, pages 1250-1259

Drug interaction

Decreased metabolism

* Ritonavir * ketoconazole* itraconazole* clarithromycin

Increased metabolism

* Rifampin* Carbamazepine * phenytoin

Dabigatran also should be used in caution with amiodarone and verapamil

Gonsalves WI, Pruthi RK, Patnaik MM. The new oral anticoagulants in clinical practice. Mayo Clin Proc. 2013;88(5):495–511

Indications§ Life threatening bleeding§ Prior to invasive procedures § Suspected overdose§ Non compliance

Coagulation assays & NOACs

Dabigatran Rivaroxaban Apixaban Edoxaban Betrixabban

PT Insensitive Prolonged Lower effect

aPTT

TT

ECT

Anti-FactorxaChromogenic assay

PT:Prothrombin time; aPTT:activated Partial Thromboplastin time; TT: Thrombin time; ECT:Ecerin clotting time

Prothrombin time(PT)§ Variable effect – None to prolonged time1

§ Insensitive to Dabigatran1

§ Rivaroxaban - Prolonged PT indicate excess risk of bleeding1

§ Apixban – significantly lower effect1

§ Edoxaban – no known relationship between PT elevation and bleeding risk1

§ Betrixaban – Insensitive, at antithrombotic concentration2


1-Tripodi A. The laboratory and the direct oral anticoagulants. Blood. 2013;121(20):4032-40352-Chan etal. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism.Vascular Health and Risk Management 2015:11 343–351

Activated Partial Thromboplastin Time( aPTT)§ Dabigatran –Variably prolonged -?quantitative

assessment of level and activity1

§ Rivaroxaban – slightly prolonged but no known relation to bleeding risk 1

§ Apixaban – slightly prolonged but no known relation to bleeding risk 1

§ Edoxaban –prolonged but no known relation to bleeding risk1

§ Betrixaban – Insensitive2


1-Tripodi A. The laboratory and the direct oral anticoagulants. Blood. 2013;121(20):4032-40352- Chan etal. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vascular Health and Risk Management 2015:11 343–351

Thrombin time(TT) § Dabigatran – too sensitive § Important parameter when Normal – Excludes

clinically relevant Dabigatran concentration § Factor Xa Inhibitors – unaffected § Hemoclot® - modified ( dilute) TT – can be used for

dabigatran measurement

Coagulation related studies & NOACs

Tripodi A. The laboratory and the direct oral anticoagulants. Blood. 2013;121(20):4032-4035

Ecarin Clotting Time( ECT)§ Dabigatran - Direct measurement and monitoring § Factor Xa inhibitors – not affected § Draw back - Lack of access


Nowak G. The ecarin clotting time, a universal method to quantify direct thrombin inhibitors. Pathophysiol Haemost Thromb. 2003;33(4):173-183

Anti-Factor Xa Chromogenic Assay§ Dabigatran – not applicable1,2

§ Rivaroxaban and Apixaban – Optimal method of measuring their effects1,2

§ Edoxaban – No threshold values for bleeding or thrombosis1,2

§ Betrixaban – sensitive and used to measure antithrombotic effect and quantitation3


1-Tripodi A. The laboratory and the direct oral anticoagulants. Blood. 2013;121(20):4032-40352-Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association practical guide on the use of new oral anticoagulants

in patients with non-valvular atrial fibrillation. Europace. 2013;15(5):625-6513-Chan etal. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vascular Health and Risk Management 2015:11 343–351

ØNo FDA approved diagnostic tests ØPT/aPTT- don’t reflect NOAC concentration ØUse normal PT – to exclude factor Xa inhibitors

anticoagulation effects ØUse normal aPTT- to exclude factor Xa inhibitors

anticoagulation effects ØUse normal TT–to exclude any anticoagulation effect

for DTIs

Summery Coagulation assays & NOACs

ØDabigatran measurement – Use Hemoclot® ØDabigatran effect measurement and monitoring -

Ecarin clotting time( ECT) ØRivaroxaban, Apixaban, Edoxaban, and Betrixaban

activity- Anti Xa chromogenic assay (locally calibrated)

Summery Coagulation assays & NOACs

• Literature review/Evidence of efficacy and safety of NOACs. - RCTs of NVAF - RCTs of VTE treatment .- Comparison of different NOACs in real world data .

• Role of NOACS in current Practice guidelines .• Practice pearls in selecting and dosing NOACS .

Outline

* Dabigatran, rivaroxaban, apixaban and edoxaban are currently the only FDA approved NOACs for treatment of NVAF.

* 4 large multicenter RCTs comparing VKAs Vs NOACs .* Non Valvular A fib .* Primary endpoint of efficacy is composite of any stroke or

systemic embolism. * Major bleeding was defined as bleeding resulting in

transfusion of more than 2 units of blood, drop of hemoglobin more than 2 g/dL , or symptomatic bleeding in a critical area or organ

Stroke prevention in A fib

Ruff et al., The Lancet, 2013

StudyNOACDrug

Doses

Design MedianAge(Y)

#ofPatients

TTRTimein

therapeutic range

%

Medianfollowuptime

(Y)

CHADS2score

Primaryoutcome

ForEfficacy

Safetyoutcome

RE-LYDabigatran

150mgor110mgtwicedaily

Openlabelbutblinded

toendpointevaluation

71.5 18113 67 2.0 2.1 AllStrokeorsystemicembolism

Majorbleeding

ROCKET–AFRivaroxaban

20or15mgdaily

Doubleblind

73 14264 58 1.9 3.5 AllStrokeorsystemicembolism

Majorandnonmajorclinicallyrelevantbleeding

ARISTOTLEApixaban

5or2.5mgtwicedaily

Doubleblind


Majorbleeding

ENGAGE-AFIBTIMI48Edoxaban

60or30mgdaily

Doubleblind


Majorbleeding

StudyNOACDrug

Doses

Design MedianAge(Y)

#ofPatients

TTRTimein

therapeutic range

%

Medianfollowuptime

(Y)

CHADS2score

Primaryoutcome

ForEfficacy

Safetyoutcome

RE-LYDabigatran


Openlabelbutblinded


71.5 18113 67 2.0 2.1 AllStrokeorsystemicembolism

Majorbleeding


20or15mgdaily

Doubleblind



ARISTOTLEApixaban

5or2.5mgtwicedaily

Doubleblind


Majorbleeding


60or30mgdaily

Doubleblind


Majorbleeding

StudyNOACDrug

Doses

Design MedianAge(Y)

#ofPatients

TTRTimein

therapeutic range

%

Medianfollowuptime

(Y)

CHADS2score

Primaryoutcome

ForEfficacy

Safetyoutcome

RE-LYDabigatran


Openlabelbutblinded


71.5 18113 67٪ 2.0 2.1 AllStrokeorsystemicembolism

Majorbleeding


20or15mgdaily

Doubleblind

73 14264 58٪ 1.9 3.5 AllStrokeorsystemicembolism


ARISTOTLEApixaban

5or2.5mgtwicedaily

Doubleblind


Majorbleeding


60or30mgdaily

Doubleblind


Majorbleeding

StudyNOACDrug

Doses

PrimaryoutcomeForEfficacy

(strokeor systemicembolism)

SafetyoutcomecomparedtoVKAs

RE-LYDabigatran


150 mg dose was superior to VKA

SimilarratesofMajorbleeding

110 mg dose was non-inferiorto VKA

Lower rateof majorbleeding


20or15mgdaily

non-inferior to VKA SimilarratesofMajorandnonmajorclinicallyrelevant

bleeding

ARISTOTLEApixaban

5or2.5mgtwicedaily

superior to VKA Lower rateofmajor bleedingLower all-causemortality


60or30mgdaily

non-inferior to VKA Lower rateofMajorbleeding

StudyNOACDrug

Doses

PrimaryoutcomeForEfficacy

(strokeor systemicembolism)

SafetyoutcomecomparedtoVKAs

RE-LYDabigatran


150 mg dose was superior to VKA

SimilarratesofMajorbleeding

110 mg dose was non-inferiorto VKA

Lower rateof majorbleeding


20or15mgdaily

non-inferior to VKA SimilarratesofMajorandnonmajorclinicallyrelevant

bleeding

ARISTOTLEApixaban

5or2.5mgtwicedaily

superior to VKA Lower rateofmajor bleedingLower all-causemortality


60or30mgdaily

non-inferior to VKA Lower rateofMajorbleeding

•Published in the Lancet December 2013. Meta-analysis of 4 Randomized controlled studies included 71 683 patients

Stroke or systemic embolic events in large NOAC trials, vs warfarin


19% reduction

RR (95%CI) p

EfficacyIschaemic strokeHaemorrhagic strokeMyocardial infarctionAll-cause mortality

0·92 (0·83–1·02) 0·100·49 (0·38–0·64) <0·00010·97 (0·78–1·20) 0·770·90 (0·85–0·95) 0·0003

SafetyIntracranial haemorrhageGastrointestinal bleeding

0·48 (0·39–0·59) <0·00011·25 (1·01–1·55) 0·043

10·2 20·5

FavourswarfarinFavoursNOAC


Secondary efficacy and safety outcomes in large NOACs trials vs. VKAs

10% reduction

50 % reduction


Major bleeding events in large NOAC trials, vswarfarin

RE-LY

What else we learn from RTCs of NOACS in NF A Fib

* All NOACS has lower incidence IC bleeding .

* NOACS has Higher risk of GI bleeding (except Apixaban).

* Patient with Cr CL less than 30 were excluded , patients with Cr CL less than 50 % relatively underrepresented .

* Patients on dual anti platelet therapy were excluded .

* Dabigatran dose 75 mg BID that was approved by FDA for patient Cr CL 15-30 was not studied in outcome based RCTs .


NOACS RCTS in VTE

* RCTs with Non inferiority design compared dabigatran, rivaroxaban, apixaban and edoxaban to standard treatment LMWH/VKAs or UFH/VKA in patients with acute VTE .

* The primary efficacy outcome was recurrent symptomatic VTE and/or VTE-related deaths .

* The primary safety outcome was major bleeding or combined major and clinically relevant non major bleeding bleeding .

der Hulle et all. J Thromb Haemost. 2014;12(3):320-328

StudyNOACDrugNOACDose

DesignofRCTs

PatientsN

Averageage

ParenteralTreatment

TTR%

PrimaryEfficacyoutcome

PrimarySafetyoutcome

RE-COVER1Dabigatran150mgBID

Double–blind 2539 55 HeparinAt least5days

60 NotinferiortoVKA Similarincidenceofmajorbleeding

EinsteinDVTRivaroxaban

15mgBIDfor21daysthen20mgoncedaily

Open-label,assessorblind

3449 56 None 58 NotinferiortoVKA Similarincidenceofmajorandclinicalrelevantbleeding

EinsteinPERivaroxaban

15mgBIDfor21daysthen20oncedaily



AmplifyApixaban

10mgBIDfor7daysthen5mgBID

Doubleblind 5395 57 None 61 NotinferiortoVKA Significantreductioninmajorbleeding

Hokusai–VTEEdoxaban

60mg

Double–blind 8240 56 HeparinorLMWHatleast5days

64 NotinferiortoVKA Significantreductioninmajorandclinicalrelevantbleeding


DesignofRCTs

PatientsN

Averageage

ParenteralTreatment

TTR%




Double-blind 2539 55 Heparin 60 NotinferiortoVKA Similarincidenceofmajorbleeding

EinsteinDVTRivaroxaban15mgBIDfor21daysthen20mgoncedaily



EinsteinPERivaroxaban15mgBIDfor21daysthen20oncedaily



AmplifyApixaban10mgBIDfor7daysthen5mgBID


Hokusai–VTEEdoxaban60mg(or30mgdailyifhigherriskofbleeding)

Double–blind 8240 56 Heparin 64 NotinferiortoVKA Significantreductioninmajorandclinicalrelevantbleeding


DesignofRCTs

PatientsN

Averageage

ParenteralTreatment

TTR%
















DesignofRCTs

PatientsN

Averageage

ParenteralTreatment

TTR%















* NOACs have a comparable efficacy to that of VKAs.

* Slight but significantly lower risk of major bleeding.

* Needed to treat with NOACs versus VKAs to prevent one major bleed was 149 (relatively high ) .

* Cancer and CKD patients were underrepresented .

der Hulle et all. J Thromb Haemost. 2014;12(3):320-328

Meta-Analysis of 5 RCTs of NOACs vsVKAs in VTE

* 4 NOACS are approved for DVT prophylaxis in major orthopedic surgery like THA and TKA .

* Only Betrixaban is approved for DVT prophylaxis in medical patients .

* Not approved for stroke prevention in valvular Afib .

* Not approved for ACS management .

* Observational evidence of efficacy in HIT –not FDA approved for this indication .

NOACs in other indications

* Double blinded double dummy RCTs compared Enoxaparin 40 mg for 10 day to 35-42 days of Betrixaban 80 mg . First dose 160 mg

* Patients hospitalized for medical reason (CHF, infection , respiratory failure --).

* Reduced mobility .* 75 yo , elevated D dimer , have hx of VTE or hx of

cancer .

APEX trial

Primary Efficacy EndpointCohort 1: D-Dimer ≥ 2 x ULN

Composite of Adjudicated Asymptomatic Proximal DVT, Symptomatic Proximal or Distal DVT, non-fatal PE, or VTE-related Death

0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

10%

Enoxaparin (N=1,956) Betrixaban (N=1,914)

Even

t rat

e (%

)

ARR = 1.59%

n=132

8.49%

6.90%NNT = 62.9

p=0.054

P-values reported using the Mantel-Haenszel test stratified for dosing criteria (ie. No adjustment, renal insufficiency, P-gp inhibitor).Symptomatic events from Day 1 till Day 42 or the date of Visit 3, if Visit 3 occurred before Day 42; Asymptomatic DVT between Day 32 and 47.

RRR = 19.4%

n=166

50

Gibson et. al. ISTH SSC 2016 – May 27, 2016

Primary Efficacy EndpointCohort 3: Overall Efficacy Population

0%

2%

4%

6%

8%

10%

Enoxaparin (N=3,174) Betrixaban (N=3,112)

Even

t rat

e (%

)

n=223 n=165

7.03%

5.30%

p=0.006

P-values reported using the Mantel-Haenszel test stratified for dosing and entry criteria (ie. No adjustment, renal insufficiency, or P-gp inhibitor / DD > 2x ULN or DD < 2x ULN).Symptomatic events from Day 1 till Day 42 or the date of Visit 3, if Visit 3 occurred before Day 42; Asymptomatic DVT between Day 32 and 47.

NNT = 57.8

Composite of Adjudicated Asymptomatic Proximal DVT, Symptomatic Proximal or Distal DVT, non-fatal PE, or VTE-related Death

51


Comparison to Previous Novel Oral Anticoagulant Trials of Extended Thromboprophylaxis in Acute Medically Ill Patients

p<0.001

3.1% 2.7%

5.7%

4.4%

7.03%

5.3%

0.2% 0.5% 0.4% 1.1%

0.57% 0.67%

Inci

denc

e (%

) VTE

Even

ts

Major Bleeding

ADOPTApixaban

MAGELLANRivaroxaban

APEXBetrixaban

Enoxaparin Apixaban Enoxaparin Rivaroxaban Enoxaparin Betrixaban

p=0.04 p<0.001 p=0.55

p = 0.44

p = 0.02

p* = 0.006

* Overall efficacy population analysis used for comparison purposes

RRR = 12.9%

RRR = 22.8%

RRR* = 24.0%

0

8

2

4

52


* 2016 ACCP Guidelines for VTE treatment recommend NOACS over VKAs in patients without cancer (grade 2B) . Based on less bleeding with NOACs and greater convenience.

* Patients with caner and VTE , LMWH is recommended over NOACs or VKAs .

* When using Dabigatran and Edoxaban for VTE treatment, 5-10 days of parenteral anticoagulation should precede the use of NOACS for that indication

NOACS in clinical practice Guidelines

Kearon ; el all Chest February 2016, Vol 149, No. 2

*Clinically stable with good cardiopulmonary reserve.

* Low risk for bleeding , No recent bleeding.

*No severe renal or liver disease, or PLT less than 70 K.

*Expected to be compliant with treatment.

* the patient feels well enough to be treated at home.

*No elevated cardiac markers or R heart strain.

Treating low risk PE as Outpatient ACCP Guidelines

Kearon ; el all Chest February 2016, Vol 149, No. 2

* Non valvular A fib and CHA2DS2-VASc score of 2 or greater , oral anticoagulation is recommended with VKAs (level A ) or NOACs (grade B) .

* In nonvalvular AF patients unable to maintain a therapeutic INR level with warfarin , NOACs is recommended .

* Renal function need to be assessed before starting NOACs * Patients on dialysis , CrCl less than 15 or who has

prosthetic valve should be treated with VKAs not NOACs .

2014 AHA/ACC guidelines for Afib management

January CT et al. 2014 AHA/ACC/HRS guideline Circulation. 2014;130(23):2071-2104

2014 AHA/ACC guidelines for Afib management define this population as any patient with :

* Rheumatic mitral stenosis, * Prosthetic or bioprosthetic valve replacement * Mitral valve repair . Aortic stenosis, aortic regurgitation and mitral regurgitation are not considered vulvar Afib

Valvular AFIB

January CT et al. 2014 AHA/ACC/HRS guideline Circulation. 2014;130(23):2071-2104

* In NVAF patient older than 65 or CHADS2 more than 1 , NOACs is recommended over VKAs (strong recommendations , high quality evidence ) .

* Exceptions- Patients with a mechanical prosthetic valve, rheumatic mitral stenosis or Cr Cl of 15-30.

* Patient above 75 y should receive lower dose of dabigatran 110 mg (not available in USA )

2014 Canadian Cardiovascular society guidelines for A fib management

Verma ;el all Can J Cardiol. 2014;30(10):1114-1130.

-Retrospective Analysis Comparing the Safety and Efficacy of NOACs in Afib by creating 3 matched cohorts using administrative data

Rivaroxaban versus dabigatran [N=31,574] Apixaban versus dabigatran [N=13,084] Apixaban versus rivaroxaban [N=13,130]

Favor RivaroxabanFavor Apixaban

0.851.05 (0.64, 1.72)1.21N=6,565

Apixaban

1.03N=6,565

Rivaroxaban

Favor DabigatranFavor Apixaban

0.410.82 (0.51, 1.31)1.22N=6,542

Apixaban

1.17N=6,542

Dabigatran

Favor DabigatranFavor Rivaroxaban

0.991.00 (0.75, 1.32)1.12N=15,787

Rivaroxaban

1.03N=15,787

Dabigatran

Retrospective Analysis Comparing the Safety and Efficacy of NOACs: Results

59Noseworthy PA et al. Chest. 2016. doi:10.1016/j.chest.2016.07.013

Event Rate per 100 Person-Years PHazard Ratio (95% CI)

vs.

vs.

vs.

1.00.0 0.5 1.5 2.0

1.0

Direct comparison Dabigatran , apixaban and Rivaroxaban

60

Favor RivaroxabanFavor Apixaban

<0.0010.39 (0.28, 0.54)2.01N=6,565

Apixaban

4.55N=6,565

Rivaroxaban

Favor DabigatranFavor Apixaban

<0.0010.50 (0.36, 0.70)2.06N=6,542

Apixaban

3.25N=6,542

Dabigatran

Favor DabigatranFavor Rivaroxaban

<0.011.30 (1.10, 1.53)3.77N=15,787

Rivaroxaban

2.58N=15,787

Dabigatran

0.0 0.5 1.5 2.0

Event Rate per 100 Person-Years PHazard Ratio (95% CI)

vs.

vs.

vs.

Noseworthy PA et al. Chest. 2016. doi:10.1016/j.chest.2016.07.013

JAMA Intern Med. 2016;176(11):1662-1671. doi:10.1001/jamainternmed.2016.5954

* NOACs or VKs * NOACs are safe in mild to moderate CKDs.* In dialysis No RCT to show benefit in VKAs or NOACS.

2016 ESC guidelines A fib

ESC 2016 guidelines for A fib European Heart Journal, Volume 37, Issue 38, 7 October 2016, Pages 2893–2962,

FavorNOAC FavorVKA FavorLMWH

LabileINRdespitecompliance(PoorTTR)

Severerenalinsufficiency(GFR<30)

Pregnancy

Lowerintracranialbleedingrisk Dualantiplatelettherapy Activecancer

NoinitialparenteraltreatmentforVTE(rivaroxabanandapixabanonly)

Mitralstenosis recurrentDVTonoraltreatment

Preferencenottohavefrequentmonitoring

ProstheticValve liverdysfunctionwithelevatedINR

Lessdrugandfoodinteraction Costisaconcern

ConcernaboutGIbleeding

PoorCompliance

EstablishedpatientwithgoodTTR(>65%)

Practice pearls (choice of anticoagulant )

FavorNOAC FavorVKA FavorLMWH

LabileINRdespitecompliance(PoorTTR)

Severerenalinsufficiency(GFR<30)or dialysispatients

Pregnancy

Lowerintracranialbleedingrisk Dualantiplatelettherapy Activecancer

NoinitialparenteraltreatmentforVTE(rivaroxabanandapixabanonly)

Rheumaticmitral disease,ProstheticValve

recurrentDVTonoraltreatment

Preferencenottohavefrequentmonitoring

Extremeofweight liverdysfunctionwithelevatedINR

Lessdrugandfoodinteractions Costisaconcern

ConcernaboutGIbleeding

PoorCompliance

EstablishedpatientwithgoodTTR(>65%)

Practice pearls (choice of anticoagulant)

Dabigatran Rivaroxaban Apixaban Edoxaban

History of GI bleeding

✖ ✖ ✓ ?

Reversal agent preferred

✓

Kidneydysfunction

✖ ✓

Daily doses preferred

✓ ✓

Higher risk of bleeding

✓ ✓

GFR above 90 ✖

Choice of NOACS

FDA Approved dosing A fib

Lexicomp Online® , Lexi-Drugs® , Hudson, Ohio: Lexi-Comp, Inc.; March 1, 2017

FDA Approved dosing VTE

Lexicomp Online® , Lexi-Drugs® , Hudson, Ohio: Lexi-Comp, Inc.; March 1, 2017

Off-Label Dosing of NOACS andAdverse Outcomes

5738 patients in 242 sites in The ORBIT-AF II Registry

* a monoclonal antibody that binds and neutralizes dabigatran .approved by FDA in 2016.

* (RE-VERSE AD) trial of 90 patients on dabigatran who either were bleeding or needed an urgent procedure.

* Idarucizumab was able to normalize coagulation studies in 88-98% of patients within minutes.

* it restored hemostasis in all bleeding patients and in 33 out of 36 patients who needed to undergo procedures .

* Cost 3500-4500 a dose .

Idarucizumab, Praxbind

Pollack ;et all The New England journal of medicine. 2015.

• Under review by FDA . Not available currently . • Inactive Factor Xa-like protein that binds to NOACS • 67 patient with major bleeding from rivaroxaban or apixaban .• effective hemostasis occurring in 79% of patients

Connolly ; et all. New England Journal of Medicine. 2016;375(12):1131-1141

* Under review by FDA . Not available currently . * Inactive Factor Xa infusion that showed promise in

reversing major bleeding from 67 patients taking rivaroxaban or apixaban .

* effective hemostasis occurring in 79% of patients

* Connolly ; et all. New England Journal of Medicine. 2016;375(12):1131-1141

Andexanet Alfa

* 4-factor PCC (II, VII, IX, X) Kcentra (approved for VKAs reversal ) is recommended in life-threatening bleeding related to NOACs by The European Heart Rhythm Association Guidelines 2014.

* It have shown efficacy in reversing their anticoagulation effect in animal models and studies on normal volunteers.

* It is available at KU MC (cost ~ 3200 $ a dose )

Prothrombin complex concentrates

* In December 2014 point of care INR device that was used in ROCKET AF were withdrawn by FDA due to falsely lower INR results .

* Some authors called ROCKET AF results into question as adjusting VKA to higher level may contributed to higher bleeding rate in VKAs arm

* FDA reviewed data and determined no change in drug label is needed .

Controversies in NOACS

Controversies of NOACspost marketing data

* 2016 JAMA published Retrospective new-user cohort study of 118 891 Medicare patients with nonvalvular who started either Rivaroxaban or Dabigatran for stroke prevention .

* Study concluded Treatment with rivaroxaban 20 mg once daily was associated with statistically significant increases in ICH and major gastrointestinal bleeding, compared with dabigatran 150 mg twice daily.

* NOACs are at least as effective as VKAs in A fib, VTEs treatment and may be safer .

* All NOACs cause less ICH .* Apixaban may have favorable efficacy /safety profile

especially in patients with CKD .* Be aware of FDA approved dosing for NOACS .* Be Aware of drug-drug interactions .

Summary

§ Compliant § Commercial insurance § Apixaban 10 mg oral BID for 7 days followed by 5 mg

BID was prescribed § Duration – three months

Case conclusion

Questions ?

Documents

Paradigm Shift In Oral Anticoagulation –Non-Vitamin K Oral ... · 1. Cabral KP. Pharmacology of the new target-specific oral anticoagulants. J ThrombThrombolysis. 2013;36(2):133-140