The changing landscape of anticoagulation
1 / 49

The Changing Landscape of Anticoagulation - PowerPoint PPT Presentation

  • Uploaded on

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

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
Download Presentation

PowerPoint Slideshow about ' The Changing Landscape of Anticoagulation' - jeremy-good

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
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


  • 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


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


  • 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

  • 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

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



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


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












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

  • 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

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

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

  • 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

  • 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

  • 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 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


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


  • 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


  • FDA to review apixaban on June 28, 2012

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

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

  • 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

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




Delay next dose

or discontinue

Symptomatic Treatment


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