Br J Haematol. 2008 Jun;141(6):757-63

A review of guidelines and update in emerging therapies

Brian Spoelhof, PharmDApril 19, 2012

The presenter has no actual or potential conflicts to disclose

Summarize the indications for anticoagulation

Describe the pharmacology of new oral anticoagulants

Evaluate the data that led to the approval of the new oral anticoagulants

Discuss the advantages and disadvantages of new anticoagulants;

Examine new potential indications for the new anticoagulants.

Anticoagulation Guidelines Atrial Fibrillation Post-op

Orthopedic Surgery

Pharmacology of current options

Dabigatran Rivaroxaban Apixiban Summary Questions

Oral

Safe Effective

Easy

Reversible

Common Pathway

Tissue Damage

Surface Contact

Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008

Vitamin K Antagonist

Unfractionated Heparin (UFH)

Low Molecular Weight Heparin (LMWH)

Direct Thrombin Inhibitors

Factor Xa Inhibitors

Warfarin

Heparin

Enoxaparin

Bivalirudin ArgatrobanDabigatranFondaparinu

xRivaroxaban

Apixiban

Vitamin K Antagonist

Narrow Therapeutic Genetic variation Drug interactions Food interactions

Required monitoring

Slow onset of action

Protein Half Life (Hours)

Prothrombin (II)

60-100

Factor VII 6-8

Factor IX 20-30

Factor X 24-40

Protein C 8-10

Protein S 40-60

Is this the perfect anticoagulant?

Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008

AAOS – American Academy of Orthopedic Surgeons Updated September 2011 Recommends no specific agent

ACCP – American College of Chest Physicians Updated February 2012

Hip Fracture Surgery Total Hip Replacement Total Knee Replacement

LMWH (preferred), Fondaparinux, Warfarin (INR 2-3), Dabigatran*, Rivaroxaban*, Apixaban*

* Not recommend in hip fracture surgery

Chest. 2008 Jun;133AAOS VTE Prevention Guidelines

ACCP and ACCF/AHA /HRS guidelines fairly similar

Risk Stratification C – Congestive heart failure H - Hypertension A – Age ≥ 75 D - Diabetes Sx2 – Prior stroke or TIA x 2

J Am Coll Cardiol. 2011 Mar 15;57(11):1330-7Chest. 2008 Jun;133

CHADS2 score of 0 Aspirin 81 to 325 mg daily

CHADS2 score of 1 Aspirin 81 to 325 mg daily plus clopidogrel or Dabigatran or warfarin titrated to INR of 2.0-3.0

CHADS2 score 2 or greater Dabigatran or warfarin titrated to INR of 2.0-3.0

J Am Coll Cardiol. 2011 Mar 15;57(11):1330-7Chest. 2008 Jun;133

Oral anticoagulation preferred over dual antiplatelet therapy

Dabigatran preferred over warfarin, except Mitral valve stenosis Stable coronary artery disease Intracoronary stents

Dabigatran – Pradaxa Direct Thrombin Inhibitor Approved to prevent stroke and systemic embolism

nonvalvular atrial fibrillation

Rivaroxaban – Xarelto Factor Xa Inhibitor Approved to prevent stroke and systemic embolism

nonvalvular atrial fibrillation and Postoperative thromboprophylaxis

Apixaban Factor Xa Inhibitor Not currently approved

Rivaroxaban, Package InsertDabigatran, Package Insert

Indication: Prevent stroke and systemic embolism

nonvalvular atrial fibrillation

Dosage: CrCl > 30 mL/min: 150 mg Twice Daily Renal: Next slide

Dyspepsia

Dabigatran, Package Insert

CrCl 15 – 30 mL/min: 75 mg Twice Daily November 2011

Consider reduced dose (75 md twice daily) in patients with moderate renal impairment (30-50 mL/min) and concurrently taking ketoconazole or dronedarone.

Assess renal function prior to starting and in patients ≥ 75 years old CrCl or < 50 mL/min

Use with extreme caution in patient greater than 80

Dabigatran, Package Insert

Dabigatran

Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008

Monitoring:aPTT

Qualitative not Quantitative

TT (Thrombin Time) Linear dose

relationship Not as readily

available

PharmacokineticsProdrugRapid absorptionTime to peak: 1-2 hoursHalf-Life: 12-17 hours

Longer in renal impairment

Dabigatran, Package Insert

Randomized, Dose blinded/regimen unblinded, noninferiority trial

Dabigatran 110 mg twice daily vs. Dabigatran 150 mg twice daily vs . Warfarin titrated to INR

n = 18,113

N Engl J Med. 2009 Sep 17;361(12):1139-51

N Engl J Med. 2009 Sep 17;361(12):1139-51

N Engl J Med. 2009 Sep 17;361(12):1139-51

Increased efficacynoninferior bleeding

Noninferior efficacy lower bleeding

No known reversal agent Study of 12 healthy individuals

Prothrombin Complex Concentrate No effect on aPTT or TT

Supportive care Blood Fluid (to support kidney function) Possible dialysis

 Circulation. 2011 Oct 4;124(14):1573-9

Oral direct thrombin inhibitor Requires renal adjustments More effective than warfarin Same risk of bleeding Twice daily dosing Dyspepsia Limited available monitoring No reversal

Indications: Approved to prevent stroke and systemic

embolism nonvalvular atrial fibrillation Postoperative thromboprophylaxis (Knee and

Hip) Dosage

Afib: CrCl >50 mL/min: 20 mg once daily CrCl 15 - 50 mL/min: 15 mg once daily

Post-op VTE prophylaxis Knee replacement: 10 mg once daily x 12-14 days Hip replacement: 10mg once daily x 35 days

Rivaroxaban Package Insert

PharmacodynamicsPeak 2.5-4 hours

Half Life: 3.2 – 22 hours

Metabolized via 3A4

MonitoringPT

More sensitive Varies with

different reagents Cannot be

standardizedaPTTAnti-Xa

Modified Anti-Xa being developed

Br J Clin Pharmacol. 2011 Oct;72(4):593-603Thromb Haemost. 2010 Apr;103(4):815-25

Rivaroxaban

Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008

J Thromb Haemost. 2006 Jan;4(1):121-8

Rivaroxaban directly inhibits Factor Xa

Eikelboom JS and Weitz JI. Lancet 2008.

Trial Setting

Enoxaparin regimen

Rivaroxaban regimen

DVT/PE/death (%)

RRR (%)

Symptomatic VTE (%)

RRR (%)

RECORD1 n=4541

THA 40 mg daily x 35 days

10 mg daily x 35 days

3.7 vs 1.1 70 — —

RECORD2 n=2509

THA 40 mg daily x 10–14 days

10 mg daily x 31–39 days

9.3 vs 2.0 79 1.2 vs 0.2 80

RECORD3n=2531

TKA 40 mg daily x 10–14 days

10 mg daily x 10–14 days

18.9 vs 9.6

49 2.0 vs 0.7 66

RECORD4 n=3148

TKA 30 mg BID x 10–14 days

10 mg daily x 10–14 days

10.1 vs 6.9

31 1.2 vs 0.7 NS

Turpie AG et al. 2008 International Congress on Thrombosis; June 27, 2008; Athens, Greece. Abstract O5.

Outcome Enoxaparin (%)

Rivaroxaban (%)

p

Symptomatic VTE/all-cause mortality

1.3 0.5 <0.001

Major bleed 0.2 0.3 0.305

Comparison of rivaroxaban to warfarin in patients with atrial fibrillation

Randomized, Double Blinded, Double Dummy, Noninferiority

Consideration Time in Therapeutic Range

 N Engl J Med. 2011 Sep 8;365(10):883-91

 N Engl J Med. 2011 Sep 8;365(10):883-91

 N Engl J Med. 2011 Sep 8;365(10):883-91

Prothrombin Complex Concentrate potentially reverses rivaroxaban

Study in 12 healthy males Returned to nearly normally levels within

15 minutes

 Circulation. 2011 Oct 4;124(14):1573-9

Oral direct Factor Xa inhibitor Post-op thromboprophylaxis

Superior to enoxaparin Similar rates of major bleeds

Stroke prophylaxis in atrial fibrillation Non-inferior to warfarin Less risk of major bleeding Discontinuation increases risk of

thromboembolism

Anticoagulation rapidly evolving

New option provide potential but haven’t eradicated the need for warfarin

When choosing an agent must balance compliance, risk, renal function

Oral Factor Xa inhibitor Not yet approved, no indications

Approval expected 6/28/12 Dosing:

5 mg twice daily 2.5 mg twice daily with two of the following:

Age > 80 years Weight < 60 kg SCr > 1.5 mg/dL

Apixaban vs warfarin for atrial fibrillation

Randomized, double blind, double dummy, noninferiority trial

n= 18,201patient

Apixaban awaiting FDA review

Approval expected

Apixaban reduced occurrence of stroke and systemic embolism compared to warfarin

Apixaban associated with lower risk of bleeding compared to warfarin

Warfarin has reduced secondary endpoints but risk of bleeding has not outweighed benefit

APPRAISE-2 Apixaban 5 mg BID vs Placebo post- MI No benefit

ATLAS-ACS2 TIMI 51 Rivaroxaban 2.5 mg daily or 5 mg daily vs placebo

post-MI Rivaroxaban 2.5 mg = Benefit Rivaroxaban 5 mg = No benefit

Hurlen M, et al. N Engl J Med. 2002 Sep 26;347(13):969-74

Rivaroxaban 2.5 mg daily Decreased primary endpoint

Cardiovascular Death, MI, or stroke 9.1% vs 10.7% (HR 0.84, P=0.0.02) NNT = 63

Decreased all cause mortality 2.9 % vs 4.5 % (HR 0.68, P=0.002) NNT = 63

Increased major bleeding (HR 3.46, P=0.001) 1.8% vs 0.6%(HR 3.46, P=0.001) NNH = 83

Apixaban•Better efficacy and safety•Theoretically reversible

•Twice daily dosing•Not yet approved

Rivaroxaban•Reversible•Once daily dosing

•Afib data not as strong•Early discontinuation increases events

Dabigatran•Best stroke reduction data

•Twice daily dosing•Dyspepsia/ GI Bleed•No reversal

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Undergoing Elective Hip and Knee Arthroplasty. Rosemont, IL AAOS September 24, 2011 http://www.jointcommission.org/

specifications_manual_for_national_hospital_inpatient_quality_measures/ - Specifications Manual for National Hospital Inpatient Quality Measure; The Joint Commission Surgical Care Improvement

Dabigatran [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT, November, 2011 http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf

Rivaroxaban [package insert Janssen Pharmaceuticals, Inc. Titusville, NJ 2011 http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf

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