Presented at Grand Rounds Department of Neurology Loyola University Health System Maywood, Illinois 60153 September 30, 2011.

Presented at

Grand RoundsDepartment of Neurology

Loyola University Health SystemMaywood, Illinois 60153

September 30, 2011

DabigatranDabigatran and other and other

New Oral AnticoagulantsNew Oral Anticoagulants

Jeanine M. Walenga, PhDProfessor, Thoracic-CV Surgery and Pathology

Co-Director, Hemostasis and ThrombosisResearch Laboratories

Loyola University Chicago

Loyola University Chicago

LOYOLAUNIVERSITYHEALTH SYSTEM

Currently Available AnticoagulantsCurrently Available Anticoagulants

DRUG CLINICAL USE• Warfarin Long-term AC, stroke

prevention in AF

• Heparin VTE, ACS, CPB, PCI• LMW heparins VTE prevention• Lepirudin (DTI) HIT• Bivalirudin (DTI) HIT, PCI• Argatroban (DTI) HIT, PCI

Some of the New Anticoagulants

Anti-FXa– Rivaroxaban (o)– Apixaban (o)– Edoxaban (o) – Otamixaban (p)– LY-517717 (o)– DX-9065a (p)– Betrixiban (o)– TK-442 (o)

Anti-Flla (anti-thrombin)– Dabigatran (o)– Odiparcil (o)– Flovagatran (p)– Pegmusirudin (p)– Peg-hirudin (p)– Desirudin (p)

O:Oral, P:Parenteral

Oral Anticoagulant Target SitesOral Anticoagulant Target Sites

AntithrombinAntithrombin

FibrinogenFibrinogen

Factor II(Prothrombin)

Factor II(Prothrombin)

FibrinFibrin

Factor IIa(Thrombin)Factor IIa

(Thrombin)

Factor XFactor X

Factor IXFactor IX Factor VIIFactor VII

Anti-FXa drugs•Apixaban•Betrixaban•Edoxaban•Rivaroxaban•LY 517717•TAK 442•YM 150

Anti-FIIa drugs•Dabigatran

•Ximelagatran•AZD 0837

Factor XaFactor Xa

VKA drugs•Tecarfarin•Warfarin

FVIIaFVIIa

FIXaFIXa

Features Warfarin New Agents

Onset Slow RapidDosing Variable FixedIndications Same SameFood effect Yes NoDrug interactions Yes YesMonitoring Yes NoHalf-life Long ShortAntidote Yes No

Features Warfarin New Agents

Onset Slow RapidDosing Variable FixedIndications Same SameFood effect Yes NoDrug interactions Yes YesMonitoring Yes NoHalf-life Long ShortAntidote Yes No

Comparison of NEW ORAL ANTICOAGULANTS

with WARFARIN

Rivaroxaban

• Direct, specific, competitive factor Xa inhibitor

• Rapid onset within 2-4 hours

• High bioavailability of >80%

• Metabolized via the CYP3A4, CYP211, and P-gp transport mechanisms

• See interactions with drugs using the same metabolic pathways

• Renal and fecal eliminationPerzborn et al., J Thromb Haemost 2005.

Kubitza et al., J Clin Pharmacol 2007.

Xarelto®

Rivaroxaban: Clinical Development

Postsurgical Postsurgical prophylaxis prophylaxis

of DVTof DVT

DVT DVT TreatmentTreatment

Stroke Stroke Prevention Prevention

in AFin AFACSACS

ODIXa-KNEE EINSTEIN-DVT ROCKET-AF ATLAS ACS-TIMI 46

ODIXa-HIP EINSTEIN-EXT ROCKET-J ATLAS

ACS-TIMI 51

RECORD-1 EINSTEIN-PE

RECORD-2

RECORD-3

RECORD-4

RECORD 1-4 Summary Total Treatment Duration Pool

Symptomatic VTE and all-cause mortality

Major bleeding

1.3%1.3%

0.6%0.6%

0.2%0.2%0.4%0.4%

ARD=–0.8%p<0.001

ARD=0.2%p=0.076

13/6,200 24/6,18382/6,200 35/6,183

p-values analyzed using a Cox regression model; safety population, n=12,383

0

0.5

1.0

1.5

2.0

Inci

den

ce (%

)

Enoxaparin regimens

Rivaroxaban regimens

Primary population for analysis

Turpie AGG, et al. Presented at ASH 2008

ROCKET-AF: Stroke, Non-CNS Embolism

Study Outcome: Rivaroxaban vs Warfarin

On TreatmentN = 14,1431.70% vs 2.15% stroke rate21% reduction in stroke rate w/ rivaroxabanp = 0.015

ITTN = 14,1712.12% vs 2.42% stroke rate12% reduction in stroke rate w/ rivaroxabanp = 0.117

Study Outcome: Rivaroxaban vs Warfarin

On TreatmentN = 14,1431.70% vs 2.15% stroke rate21% reduction in stroke rate w/ rivaroxabanp = 0.015

ITTN = 14,1712.12% vs 2.42% stroke rate12% reduction in stroke rate w/ rivaroxabanp = 0.117

ROCKET-AF: Clinical Trial Outcomes

• Efficacy– Rivaroxaban: non-inferior to warfarin for SPAF

– Rivaroxaban: superior to warfarin while patients were taking study drug

• Safety– Similar rates of bleeding and adverse events

– Less ICH and fatal bleeding with rivaroxaban

• Conclusion– Rivaroxaban is a potential alternative to warfarin for

moderate or high risk AF patients

Rivaroxaban: FDA Status

• Xarelto trade name

• For the prevention of DVT/PE after orthopedic surgery:– Rivaroxaban 10 mg OD is FDA approved (July 2011)– Approved in the EU and Canada

• For the prevention of stroke in patients with atrial fibrillation:– FDA advisory committee voted to approve (Sept. 2011)

• Yes=9, No=2, Abstain=1– Recommended approval in the EU (Sept. 23, 2011)

Apixaban

• Direct, reversible FXa inhibitor

• Rapid onset, peak within 3 hrs

• Bioavailability of 51-85%

• Long half life, slightly longer in elderly (15 hrs)

• Multiple elimination pathways– 25% renal

– 75% biliary

• Metabolism via CYP3A4, SULT1AA pathways Perzborn et al., J Thromb Haemost 2005.

Kubitza et al., J Clin Pharmacol 2007.

Eliquis

Apixaban: Clinical Development

Postsurgical Postsurgical prophylaxis prophylaxis

of DVTof DVT

DVT DVT TreatmentTreatment

Stroke Stroke Prevention Prevention

in AFin AFACSACS

APROPOS Botticelli DVT dose-ranging study

ARISTOTLE APPRAISE-1

ADVANCE-1 AMPLIFY (ongoing)

AVERROES APPRAISE-2 (study terminated

because of bleeding)

ADVANCE-2 AMPLIFY-EXT (ongoing)

APPRAISE Japan

(study terminated)

ADVANCE-3

ADVANCE-2: Primary Efficacy Results

Lassen MR, et al. Presented at ISTH, Boston, MA. July 2009.

*Composite of adjudicated asymptomatic DVT by venography; objectively confirmed symptomatic DVT or PE; or death from any cause. One-sided p-value for superiority.

Apixaban 2.5mg BID(n=976)

Enoxaparin 40mg QD(n=997)

15.1 %

24.4 %

0%

5%

10%

15%

20%

25%RR: 0.62; 95% CI: 0.51-0.74

p < 0.0001*

Pri

mar

y E

nd

po

int*

(%

)

95%CI: 95%CI: 13.0-17.5%13.0-17.5%

95%CI:95%CI:21.8-27.1%21.8-27.1%

ARISTOTLE: Study Outcomes

• Treatment with apixaban as compared to warfarin in patients with AF (n>18,000) and at least one additional risk factor for stroke:– Reduces stroke and systemic embolism by 21%

(p=0.01)– Reduces major bleeding by 31% (p<0.001)– Reduces mortality by 11% (p=0.047)– Consistent effects across all major subgroups– Fewer drug discontinuations on apixaban than on

warfarin, consistent with good tolerability

Granger CB, et al. NEJM 2011;365: Aug 28Granger CB, et al. NEJM 2011;365: Aug 28

Apixaban: FDA Status

• Eliquis trade name

• For the prevention of DVT/PE after orthopedic surgery:– No FDA approval yet– Apixaban approved in the EU

• For the prevention of stroke in patients with atrial fibrillation:– No approvals yet

Edoxaban: Clinical Development

Postsurgical Postsurgical prophylaxis of DVTprophylaxis of DVT

DVT DVT TreatmentTreatment

Stroke Prevention Stroke Prevention in AFin AF

Oral direct FXa inhibition Oral direct FXa inhibition with E for thrombophylaxis with E for thrombophylaxis after elective THR: a after elective THR: a randomized double-blind randomized double-blind dose-response study dose-response study

The Edoxaban The Edoxaban Hokusai-VTE Hokusai-VTE Study Study (ongoing) (ongoing)

Randomized, parallel-group, Randomized, parallel-group, multicenter, multinational multicenter, multinational Phase II study comparing E, Phase II study comparing E, an oral factor Xa inhibitor, an oral factor Xa inhibitor, with warfarin for SPAFwith warfarin for SPAF

STARS J-1 STARS J-1 ENGAGE AF-TIMI 48 ENGAGE AF-TIMI 48

STARS J-2 STARS J-2 (completed (completed June 2011; unpublished) June 2011; unpublished)

Safety of edoxaban, an oral factor Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with Xa inhibitor, in Asian patients with

NVAFNVAF

STARS E-3 STARS E-3 (completed (completed Feb. 2010; unpublished)Feb. 2010; unpublished)

STARS J-4 STARS J-4 (completed (completed Feb. 2010; unpublished) Feb. 2010; unpublished)

STARS J-5 STARS J-5 (completed (completed March 2010; unpublished) March 2010; unpublished)

Edoxaban: FDA Status

• Lixiana trade name

• For the prevention of DVT/PE after orthopedic surgery:– No FDA approval yet– Edoxaban approved in Japan

• For the prevention of stroke in patients with atrial fibrillation:– No approvals

Dabigatran Etexilate

• Specific, competitive, reversible univalent thrombin inhibitor

• Pro-drug converted to active form

• Rapid onset within 2 hours

• Low bioavailability, 3.5-5%

• Low protein binding

• Half life 12-17 hours

• Renal clearance as glucuronic acid conjugate: 85%

• Metabolized by esterase catalyzed hydrolysis and P-gp transport mechanisms

Perzborn et al., J Thromb Haemost 2005.

Kubitza et al., J Clin Pharmacol 2007.

Pradaxa®

Dabigatran: Clinical Development

Postsurgical Postsurgical prophylaxis prophylaxis

of DVTof DVT

DVT DVT TreatmentTreatment

Stroke Stroke Prevention in Prevention in

AFAFACSACS

RE-MODEL RE-MODEL RE-COVER RE-COVER RE-LY RE-LY RE-DEEM RE-DEEM (unpublished)(unpublished)

RE-MOBILIZE RE-MOBILIZE RE-MEDY RE-MEDY (ongoing)(ongoing)

RE-NOVATE RE-NOVATE RE-SONATE RE-SONATE (unpublished) (unpublished)

RE-NOVATE 2 RE-NOVATE 2 (unpublished)(unpublished)

RE-LYA Non-Inferiority Trial

Atrial fibrillation with ≥ 1 Risk FactorAtrial fibrillation with ≥ 1 Risk FactorAbsence of contraindicationsAbsence of contraindications

951 centers in 44 countries951 centers in 44 countries

Atrial fibrillation with ≥ 1 Risk FactorAtrial fibrillation with ≥ 1 Risk FactorAbsence of contraindicationsAbsence of contraindications

951 centers in 44 countries951 centers in 44 countries

R

Warfarin Adjusted Warfarin Adjusted INR 2.0 – 3.0INR 2.0 – 3.0

N=6,000N=6,000

Blinded Event Adjudication

Open

Dabigatran Dabigatran 110 mg BID 110 mg BID

N=6,000N=6,000

Dabigatran Dabigatran 150 mg BID150 mg BID

N=6,000N=6,000

Blinded

Connolly SJ, et al. NEJM 2009; 361:1139-1151

RE-LY: Stroke Prevention 150 mg - 34% Fewer Strokes

0.50 0.75 1.00 1.25 1.50

Dabigatran 110 vs. Warfarin

Dabigatran 150 vs. warfarin

Non-inferiorityp-value<0.001

<0.001

Superiorityp-value 0.34

<0.001

Margin = 1.46

HR (95% CI) Warfarin betterDabigatran better

Connolly SJ, et al. NEJM 2009;361:1139-51

RE-LY: Study Outcomes

Efficacy• Both doses of dabigatran were non-inferior to warfarin on the

primary endpoint– reduction of the incidence of stroke including hemorrhagic and

systemic embolism; p<0.001

• Dabigatran 150 mg BID was superior to warfarin on the primary endpoint by 34%

– RR 0.66, 95% CI, 0.53-0.82; p<0.001

Safety• No significant difference in the rate of major bleeding for dabigatran

150 mg BID compared to warfarin– 3.11 vs 3.36 %/yr; p=0.31

• Rate of major bleeding with dabigatran 110 mg BID (2.71%/yr) was 20% lower compared to warfarin; p=0.003

RE-LY: MORTALITY REDUCTIONDABIGATRAN VS WARFARIN

• Lower death rate with dabigatran:– Vascular death

2.69% vs 2.43 and 2.28%* (p=0.04 for 150 mg)

– All cause death4.13% vs 3.75 and 3.64% (p=0.05 for 150 mg)

*Dabigatran 110 mg and 150 mg

Connolly SJ, et al. NEJM 2009;361: 1139-1151Connolly SJ, et al. NEJM 2009;361: 1139-1151

RE-LY: BLEEDINGDABIGATRAN VS WARFARIN

• More bleeding with warfarin:– Life-threatening bleeding

1.8% vs 1.2 and 1.5%* (p<0.001, 0.04)– Intracranial bleeding

0.7% vs 0.2 and 0.3% (p<0.001, <0.001)– Major plus minor bleeding

18.2% vs 14.6 and 16.4% (p<0.001, 0.002)

*Dabigatran 110 mg and 150 mg

Connolly SJ, et al. NEJM 2009; 361:1139-1151Connolly SJ, et al. NEJM 2009; 361:1139-1151

Dabigatran: FDA Status

• Pradaxa trade name

• For the prevention of DVT/PE after orthopedic surgery:– FDA approval pending– Pradaxa approved in EU and Canada

• For the prevention of stroke in patients with non-valvular atrial fibrillation (SPAF):– Pradaxa 150 mg BID FDA approved (Oct. 2010)– Pradaxa approved in EU, Canada and Japan

Dabigatran: FDA Approved Dosing

• 150 mg BID for SPAF – 150 mg for CrCl >30 mL / min– 75 mg for CrCl 15-30 mL / min

Stroke from Atrial Fibrillation

• AF is the most preventable cause of stroke:– 12-16 million will be on warfarin treatment by

2050 in the US– Clinical trials have shown stroke can be

reduced:• Placebo vs ASA = 19% • ASA vs warfarin = 30% • Placebo vs warfarin = 62% • Dabigatran vs warfarin = 34%

Dabigatran: Not Without Issues

1. No anticoagulant effect if missed dose• 2% discontinuation rate due to GI distress• Cost of drug ($240/mo vs $4/mo for warfarin)

2. No test to assess anticoagulation3. Difficult to modulate dose4. Bleeding in the elderly and renal impaired patients

(5 dabigatran related deaths in Japan)5. ‘Real world’ untested populations6. Drug interactions7. Limited data on bridging between anticoagulants8. No specific antidote 9. 0.2% increase in myocardial infarction10. Off-label use

New OACs: Immediate Practical Issues

• Is there a specific antidote for dabigatran associated bleeding?– No, still in development

• How do we manage bleeding complications associated with dabigatran?

• How can we test a patient for the presence of dabigatran?

• Are there drug interactions with dabigatran?– tPA (stroke, AMI)

– Heparins (ACS, stroke)

– Antiplatelet drugs

New OACs: ‘Real Life’ Experience

• Populations not studied in the clinical trials:– Elderly, pediatrics, pregnant– Heparin compromised (e.g., HIT)– Acute vs non-acute VTE– Chronically ill

• Common patient characteristics that influence the drug PKs and safety/efficacy of NOACs:– Co-morbid illnesses– Reduce renal function– Reduced hepatic function– Altered metabolism, gastric pH, intestinal motility,

protein binding– Extremes in body weight– Co-administered Rx drugs, dietary supplements, herbs

New OACs: ‘Real Life’ Experience

• Drug interactions with NOACs:– Potential adverse effects

• Alter the pharmacokinetics of the NOAC• Increase or decrease exposure to the NOAC• Increase bleeding risk

– Known ‘cautioned’ drugs• Proton pump inhibitors• Inhibitors or inducers of the CYP3A4 or P-gp transport

mechanisms• NSAIDs, ASA, anti-platelet drugs

– At risk patients• Cardiovascular disease• Depression• Pain• Epilepsy• Requiring antibiotics, anti-fungals, anti-malaria drugs

Dabigatran: Bleeding Management

• Short half-life• Maintain adequate diuresis• Usual supportive measures: compression, surgical

hemostasis• Dialysis (low protein binding)1

• Activated charcoal w/ subsequent charcoal filtration (in vitro data)1

• Blood products– May not be effective: replace factor deficiency (warfarin) vs

overcome an inhibitor (dabigatran)

• PCC not effective (effective against rivaroxaban)2

• rFVIIa

1vanRyn J, et al. Thromb Haemost 2010;103(6):1116-272 Eerenberg ES, et al. Circulation 2011;124:Sept 6

1vanRyn J, et al. Thromb Haemost 2010;103(6):1116-272 Eerenberg ES, et al. Circulation 2011;124:Sept 6

Dabigatran: Laboratory Testing

• Monitoring vs anticoagulant assessment– PT and aPTT

• Differing reagent sensitivities

• Not a linear association between assay values and drug level

• Not validated for association to bleeding

• aPTT may be applicable for qualitative assessment

– INR: not sensitive; not validated– TT: Super-sensitive; can identify if any drug onboard– Ecarin clotting time: results can vary depending on plasma

factors; research use only (RUO)– PiCT: RUO– Chromogenic anti-FIIa– Hemoclot: quantitative using dabigatran calibrators; FDA

approved yet?

Anticoagulant Effects of Direct Thrombin and Factor Xa Inhibitors in Retrieved Plasma

(Assay: PT)

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Tim

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ecs)

DABIGATRAN

MELAGATRAN

OTAMIXABAN

RIVAROXABAN

2 case reports of inaccurate INR values w/ dabigatran.

Baruch L, Sherman O. Ann Pharmacother 2011 Jun 28

2 case reports of inaccurate INR values w/ dabigatran.

Baruch L, Sherman O. Ann Pharmacother 2011 Jun 28

Anticoagulant Effects of Direct Thrombin and Factor Xa Inhibitors in Retrieved Plasma (Assay: APTT)

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MELAGATRAN

OTAMIXABAN

RIVAROXABAN

Anticoagulant Effects of Direct Thrombin and Factor Xa Inhibitors in Human Whole Blood (Assay: TT5UCa++)

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MELAGATRAN

OTAMIXABAN

RIVAROXABAN

Anticoagulant Effects of Direct Thrombin Inhibitors in Retrieved Plasma (Assay: Anti-IIa)

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MELAGATRAN

Anticoagulant Effects of Direct Factor Xa Inhibitors in Retrieved Plasma (Assay: Anti-Xa)

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ion OTAMIXABAN

RIVAROXABAN

(Stangier et al. ISTH 2009, Boston)

Dabigatran Calibration Curve Dabigatran Calibration Curve

0

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0 1000 2000 3000 4000

Dabigatran concentration [nM]

He

mo

clo

t th

rom

bin

clo

ttin

g t

ime

[s

]

Linear fit (30.85 +0.04948x)

95% CI

95% Prediction interval

Hemoclot Assay for DabigatranHemoclot Assay for Dabigatran

Dabigatran vs Hemoclot TT (220 mg D)

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oclo

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Linear f it (31.44 +0.1437x)

95% CI

95% Prediction interval

Dabigatran Treated PatientsDabigatran Treated Patients

The New Oral Anticoagulants:Similar Yet Different

• Thrombin Inhibitors:1. Dabigatran: pro-drug, renal clearance - twice daily

• FXa Inhibitors:1. Rivaroxaban: renal clearance - once daily2. Apixaban: hepatic clearance - twice daily3. Edoxaban: hepatic clearance - once daily

Circulation 2010;121:1523-1532Circulation 2010;121:1523-1532

The New Oral Anticoagulants: Similar Yet Different

FeaturesFeatures RivaroxabanRivaroxaban ApixabanApixaban Dabigatran Dabigatran EtexilateEtexilate

TargetTarget Xa Xa IIa

Molecular WeightMolecular Weight 436 460 628

ProdrugProdrug No No Yes

Bioavailability (%)Bioavailability (%) 80 50 6

Time to peak (h)Time to peak (h) 3 3 2

Half-life (h)Half-life (h) 9 9-14 12-17

Renal excretion (%)Renal excretion (%) 65 25 80

AntidoteAntidote None None None

• Each drug has its own effect in lab tests.• The metabolic mechanisms of each drug differ; see drug interactions.• Each drug has to be managed individually.

• Each drug has its own effect in lab tests.• The metabolic mechanisms of each drug differ; see drug interactions.• Each drug has to be managed individually.

The Future of Warfarin

1. Excellent efficacy

2. Low cost ($0.75 per day!)

3. Long track record (since 1954)

4. Centralized Anticoagulation Clinics that maintain TTRs > 60%

5. PT assay available: fast TAT, inexpensive

6. INR validated for warfarin relation to bleeding risk

7. Point-of-care testing

8. Rapid turnaround genetic testing

Conclusions1. New anticoagulants are now clinically

available and additional drugs are being developed.

2. The new oral anticoagulants rivaroxaban, dabigatran and apixaban, though costly, will provide more options for the management of VTE; however, these drugs are not superior to the standard of care.

3. For VTE prevention, heparins and warfarin will remain the standard of care for some time, especially in medical patients.

Conclusions

4. For atrial fibrillation (SPAF) the new oral anticoagulants appear to have a superior safety and efficacy profile.

5. Additional clinical trials are needed to determine the merit of these drugs beyond the ‘clinical trial’ populations, and to address unanswered questions.

6. Warfarin’s low cost, efficacy, and track record will prolong its life. Its use may decrease but it will remain a for years to come.

Regulatory Approvals

• Orthopedic surgery (THR/TKR/Hip fracture):– Dabigatran: EU, Canada– Rivaroxaban: EU, Canada, US– Apixaban: EU– Edoxaban: Japan

• Non-ortho surgery, medical patients:– No approvals

• SPAF:– Dabigatran: US, EU, Canada, Japan– Rivaroxaban: US and EU approval recommended