presented at grand rounds department of neurology loyola university health system maywood, illinois...
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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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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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Anticoagulant Effects of Direct Thrombin and Factor Xa Inhibitors in Human Whole Blood (Assay: TT5UCa++)
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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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(Stangier et al. ISTH 2009, Boston)
Dabigatran Calibration Curve Dabigatran Calibration Curve
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He
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[s
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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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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.