The changing landscape of anticoagulation
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The Changing Landscape of Anticoagulation. William D. Cahoon, Jr., PharmD, BCPS Cardiology Clinical Pharmacist VCU Health System April 12, 2012. Objectives. Review dabigatran post-marketing safety data Evaluate cardiovascular data for novel oral anticoagulants

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The Changing Landscape of Anticoagulation

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The changing landscape of anticoagulation

The Changing Landscape of Anticoagulation

William D. Cahoon, Jr., PharmD, BCPS

Cardiology Clinical Pharmacist

VCU Health System

April 12, 2012


Objectives

Objectives

  • Review dabigatran post-marketing safety data

  • Evaluate cardiovascular data for novel oral anticoagulants

  • Identify advantages and limitations of available agents

  • Discuss the practical management of oral anticoagulation


The changing landscape of anticoagulation

Dabigatran


Dabigatran

Dabigatran

Oral, direct thrombin inhibitor

Activation: Hydrolysis

Tmax: 1 hour

T1/2: 12-17 hours

Metabolism: Hydrolysis

Renal excretion: 80%

Dosing: Fixed, twice daily

Monitoring: None required

Annu Rev Med 2011;62:41-57


Dabigatran the first non warfarin

Dabigatran – The First Non-Warfarin

  • Oral direct thrombin inhibitor with no monitoring

  • FDA approved October 2010

  • RE-LY Trial demonstrated:

    • Dabigatran superior to warfarin for stroke prevention

    • Equivalent rates of major bleeding

  • By August 2011 dabigatran prescribed to 250,000 U.S. atrial fibrillation patients (~10%)


Dabigatran dosage and administration

Dabigatran Dosage and Administration

  • Note: Capsules cannot be opened, crushed, or chewed

Pradaxa Package Insert


Ismp safety alert dabigatran

ISMP Safety Alert - Dabigatran

  • 932 serious adverse events reported with dabigatran in the 1st quarter of 2011

  • 505 cases involved hemorrhage

  • Hemorrhage in elderly (median age 80)

  • “FDA and manufacturer should reevaluate dosing in the elderly”


Dabigatran post marketing

Dabigatran Post-Marketing

  • FDA investigating post-marketing reports of serious bleeding

  • 260 fatal bleeding events worldwide

  • Prompted safety advisories in several countries

  • Labeling changes in US and Europe


Dabigatran labeling changes

Dabigatran Labeling Changes

Pradaxa Package Insert – Updated 1/2012


New zealand dabigatran experience

New Zealand Dabigatran Experience

  • 7000 patients started treatment in first 2 months

  • Audit revealed 78 bleeding episodes; 12 major

  • Four contributing factors identified:

    • Prescriber error

    • Impaired renal function

    • Patient age

    • Lack of reversal agent

N Engl J Med 2012;366(9):864-6


Dabigatran and mi signal

Dabigatran and MI Signal

  • Meta-analysis revealed a significant 33% relative risk increase in MI or ACS (p=0.03)

  • Absolute risk increase was only 0.27%

  • RE-LY investigators found non-significant increase in MI with dabigatran

  • Risk may be due to warfarin comparator

Arch Intern Med 2012; Published Online

Circulation 2012;125:669-76.


Warfarin following mi

Warfarin Following MI

  • OASIS and WARIS II

  • Meta-analysis of warfarin plus aspirin

    • Associated with reduced risk of MI, stroke

    • Increase in major bleeding

  • Thienopyridines decreased uptake of warfarin for secondary ACS prevention

Ann Intern Med 2005;143:241-50


Re deem

RE-DEEM

  • Purpose: Select the dabigatran dose that balances effectiveness and bleeding risk

  • Methods: Randomized, placebo-controlled trial of patients post myocardial infarction (MI)

  • Intervention:

    • Dabigatran 50, 75, 110, or 150 mg twice daily or placebo

  • Primary Outcome: Major or clinically relevant minor bleed

  • Secondary Outcome: Incidence of cardiovascular events

Eur Heart J 2011;32:2781-9


Re deem1

RE-DEEM

Eur Heart J 2011;32:2781-9


D fine study

D-Fine Study

  • Purpose: Test a short course of dabigatran prior to PCI

  • Methods: Randomized, open-label trial of 50 patients

  • Intervention:

    • Dabigatran 110 or 150 mg twice daily or heparin (UFH)

  • Outcome:

    • 5 dabigatran patients required anticoagulation bail-out

    • UFH provided greater level of anticoagulation protection

  • Conclusion: Dabigatran may not provide sufficient anticoagulation to allow for elective PCI

Eur Soc Cardiol Congress 2011


Dabigatran prior to pci

Dabigatran Prior to PCI

BOEHRINGER INGELHEIM PHARMACEUTICALS, INC

DRUG INFORMATION UNIT

Percutaneous Coronary Intervention (PCI): During PCI, the activated clotting time (ACT) was to be measured and heparin administered as needed according to usual practice

Reference:

Data on file. Boehringer Ingelheim, Ridgefield, CT. Clinical Trial Report 1160.26.

Thromb Haemost 2010;103:1116-1127


Dabigatran post procedure

Dabigatran Post Procedure

  • Bridge therapy for AF patients typically unnecessary

  • Use of monitored anticoagulant (i.e. heparin) may be indicated in patients following major surgery

Curr Pharm Des 2010;16:3436-3441


Dabigatran considerations

No hepatic dose adjustment needed

Close renal function monitoring required

Caution in the elderly, low body weight

Questionable signal of MI risk

NOT on VCUHS patient assistance program (PAP); ~$152/mo, insurance coverage varies

Dabigatran Considerations


Novel anticoagulants

Novel Anticoagulants

TF/VIIa

X

IX

VIIIa

IXa

Xa

II

IIa

Fibrinogen

Fibrin


The changing landscape of anticoagulation

Rivaroxaban


Rivaroxaban

Rivaroxaban

Oral factor Xa inhibitor

Activation: None

Tmax: 2-4 hours

T1/2: 5-9 hours

Metabolism: Hepatic,CYP3A4

Renal excretion: 66%

Dosing: Fixed, once daily

Monitoring: None required

Annu Rev Med 2011;62:41-57


Rivaroxaban dosage and administration

Rivaroxaban Dosage and Administration

*Administer with evening meal

Xarelto Package Insert


Rocket af

ROCKET AF

  • Purpose: Compare rivaroxaban with warfarin for the prevention of stroke in nonvalvular atrial fibrillation (AF)

  • Methods: Double-blind, double-dummy non-inferiority (superiority) trial of moderate to high risk patients

  • Intervention:

    • Rivaroxaban 20 mg daily -or-

    • Warfarin (Target INR 2.5)

  • Primary Efficacy Outcome: Stroke or systemic embolism

  • Primary Safety Outcome: Major bleeding

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


Rocket af1

ROCKET AF

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


Atlas acs 2 timi 51

ATLAS ACS 2-TIMI 51

  • Purpose: Evaluate rivaroxaban as adjunctive therapy following recent ACS

  • Methods: Double-blind, placebo-controlled study of patients within 7 days post ACS

  • Intervention:

    • Rivaroxaban 2.5 mg twice daily

    • Rivaroxaban 5 mg twice daily

    • Placebo

  • Primary Outcome: Composite of death, MI, stroke

N Engl J Med 2012;366(1):9-19


Atlas acs 2 timi 511

ATLAS ACS 2-TIMI 51

  • Primary Endpoint: Rivaroxaban 2.5 mg 9.1% vs. placebo 10.7%

    (HR 0.84, p=0.02)

  • Primary Endpoint: Rivaroxaban 5 mg 8.8% vs. placebo 10.7%

    (HR 0.85, p=0.03)

N Engl J Med 2012;366(1):9-19


Atlas acs 2 timi 512

ATLAS ACS 2-TIMI 51

  • March 2012 - FDA granted priority review for the additional indication of reducing CV events post ACS

N Engl J Med 2012;366(1):9-19


X plorer

X-PLORER

  • Purpose: Compare rivaroxaban with UFH as the primary anticoagulant in elective PCI

  • Intervention (Estimated enrollment 105 pts):

    • UFH 70-100 IU/kg bolus, ACT goal 250-300 sec

    • Rivaroxaban 10 mg single dose

    • Rivaroxaban 20 mg single dose

    • Rivaroxaban 10 mg plus UFH 50 IU/kg bolus

  • Primary Outcome: Thrombosis and ischemic events

  • Estimated study completion April 2012

www.clinicaltrials.gov accessed 3/2012


Rivaroxaban prior to pci

Rivaroxaban Prior to PCI

  • Half-life 5-9 hours; once daily dosing

  • Activity does not correlate with aPTT or ACT

*Consider longer drug free interval in renal impairment


Rivaroxaban post procedure

Rivaroxaban Post Procedure

  • Should be restarted as soon as adequate hemostasis established

  • If oral medication cannot be taken following procedure consider administering a parenteral anticoagulant

Xarelto Package Insert


Rivaroxaban considerations

Avoid in moderate-severe hepatic impairment

Renal dose adjustment required

Once daily dosing may improve compliance

Potential “benefit” in ACS patients

On VCUHS PAP program; ~$151/mo, insurance coverage varies

Rivaroxaban Considerations


The changing landscape of anticoagulation

Apixaban


Apixaban

Apixaban

Oral, factor Xa inhibitor

Activation: None

Tmax: 3-3.5 hours

T1/2: 9-14 hours

Metabolism: Hepatic,CYP3A4

Renal excretion: 25%

Dosing: Fixed, twice daily

Monitoring: None required

Annu Rev Med 2011;62:41-57


Aristotle

ARISTOTLE

  • Purpose: Compare apixaban with warfarin for the prevention of stroke or systemic embolism

  • Methods: Randomized, double-blind trial of patients with at least 1 risk factor for stroke

  • Intervention:

    • Apixaban 5 mg twice daily -or-

    • Warfarin (Target INR 2.0 - 3.0)

  • Primary Efficacy Outcome: Stroke or systemic embolism

  • Primary Safety Outcome: Major bleeding

N Engl J Med 2011;365(11):981-92


Aristotle1

ARISTOTLE

  • FDA to review apixaban on June 28, 2012

N Engl J Med 2011;365(11):981-92


Appraise 2

APPRAISE-2

  • Purpose: Evaluate the role of apixaban in patients with recent acute coronary syndromes (ACS)

  • Methods: Double-blind, parallel group trial of high risk ACS patients with mono or dual antiplatelet therapy

  • Intervention:

    • Apixaban 5 mg twice daily -or-

    • Placebo

  • Primary Outcome: Composite of cardiovascular death, MI, and ischemic stroke

N Engl J Med 2011;365(8):699-708


Appraise 21

APPRAISE-2

  • Stopped early by data safety monitoring board

  • Increase in major bleed events without reduction in recurrent ischemic events

N Engl J Med 2011;365(8):699-708


Apixaban considerations

NOT FDA approved

Hepatic dose adjustment may be necessary

Renal dose adjustment unlikely

Decreased bleed rates compared with warfarin

Risk-benefit neutral in ACS

Apixaban Considerations


Choice of agent

Choice of Agent


Atrial fibrillation trial comparison

Atrial Fibrillation Trial Comparison


Characteristics of novel agents

Characteristics of Novel Agents


Patient selection

Patient Selection

Novel anticoagulants may be most appropriate for:

Unstable INRs on warfarin

Difficulty or hardship with INR monitoring

CrCl > 30 ml/min

History of good medication compliance

Patients < 75 years old

Novel anticoagulants probably not the best choice for:

Consistently therapeutic INRs on warfarin

Renal dysfunction (dabigatran and rivaroxaban)

History of significant GI disease or GI bleeding

Medication non-compliance

No prescription insurance / unable to afford co-pay


Management of bleeding

Management of Bleeding

Bleeding on Therapy

Mild

Moderate-Severe

Life-Threatening

Delay next dose

or discontinue

Symptomatic Treatment

Compression

Surgical intervention

Fluid replacement

Blood transfusion

Charcoal (overdose)

Dialysis (dabigatran)

Consider rFVIIa

or PCC

Thromb Haemost 2010;103:1116-1127


Bleeding reversal

Bleeding Reversal

  • No reversal agents or antidotes exist

  • Vitamin K and protamine should be avoided

  • Clotting factor concentrates may be an option

    • Prothrombin Complex Concentrate 50 units/kg

    • FEIBA 50-100 units/kg

    • Factor VIIa 90 mcg/kg

  • Monitor for signs of clinical improvement


Other potential indications

Post-operative prophylaxis (orthopedic)

Each agent has been evaluated in clinical trials

Only rivaroxaban FDA approved for this indication

DVT prophylaxis in medically ill

Acute venous thromboembolism treatment

Other Potential Indications

Pharmacotherapy 2011;31(12):1175-91


Notable agents in development

Notable Agents in Development

  • Edoxaban

    • Oral factor Xa inhibitor in phase III trials

    • ENGAGE AF TIMI 48 Trial

  • Otamixaban

    • IV, short-acting factor Xa inhibitor

    • Phase III TAO trial in early invasive ACS

  • plasma derived (pd)-factor Xa antidote

    • Potential antidote for factor Xa inhibitors

    • Preliminary trials showed dose dependent reversal

Pharmacotherapy 2011;31(10):975-1016

Am J Hematol 2012; e-pub ahead of print


Remaining questions

Remaining Questions

  • Real world effectiveness vs. clinical trial efficacy

  • Market uptake of multiple novel oral anticoagulants

  • Safety of triple antithrombotic therapy

  • Safety with concomitant prasugrel or ticagrelor therapy

  • Management of bleeding and identification of antidote


Summary oral anticoagulants

Summary: Oral Anticoagulants

  • Dabigatran associated with post-marketing bleed events

  • Rivaroxaban the first oral, factor Xa inhibitor to market

  • Clinical trials evaluating use in other cardiovascular indications (ACS, PCI) in addition to AF

  • Management of bleeding difficult as no antidote exists

  • Agent-specific characteristics to guide drug selection


Questions

Questions?


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