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
• Identify advantages and limitations of available agents
• Discuss the practical management of oral anticoagulation
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
• 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
Approved Dosage Forms
75 mg & 150 mg capsules
Nonvalvular Atrial Fibrillation
Normal Renal Function
(CrCl > 30 ml/min)
150 mg twice daily
Moderate Renal Impairment
(CrCl 15 – 30 ml/min)
75 mg twice daily
Severe Renal Impairment
(CrCl < 15 ml/min)
Not recommended
• Note: Capsules cannot be opened, crushed, or chewed
Pradaxa Package Insert
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
• 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
Pradaxa Package Insert – Updated 1/2012
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
• 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
• 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
• 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-DEEM
Outcomes
Placebo
(n=371)
Dabigatran
50 mg
(n=369)
Dabigatran
75 mg
(n=368)
Dabigatran
110 mg
(n=406)
Dabigatran
150 mg
(n=347)
Major or clinically
relevant minor bleed
(%)
2.4
3.5
4.3
7.9
7.8
Major bleed (%)
0.5
0.8
0.3
2.0
1.2
CV death, nonfatal
MI, stroke (%)
3.8
4.6
4.9
3.0
3.5
Eur Heart J 2011;32:2781-9
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
Procedural Bleed
BOEHRINGER INGELHEIM PHARMACEUTICALS,
INC
Risk
DRUG INFORMATION UNIT
Renal Function
Standard Risk
High Risk
Hold for 24 hours
Hold for 48-96 hours
Hold for 48 hours
Hold for 96 hours
Hold for 24-120 hours
Hold > 120 hours
Percutaneous Coronary Intervention (PCI): During PCI, the activated clotting time (ACT) was to
be measured and heparin administered as needed according to usual practice
Normal or Mild Impairment
Reference:
(CrCl
> 50Boehringer
ml/min) Ingelheim, Ridgefield, CT. Clinical Trial Report 1160.26.
Data
on file.
Moderate Impairment
(CrCl 30-50 ml/min)
Severe Impairment
(CrCl < 30 ml/min)
Thromb Haemost 2010;103:1116-1127
Dabigatran Post Procedure
Resume Dabigatran
Standard Risk
High Risk
24 hours post
48 hours post
• 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
Novel Anticoagulants
TF/VIIa
X
IX
VIIIa
Warfarin
Sites of Action
II
VII
IX
X
Rivaroxaban
Apixaban
Edoxaban
Betrixaban
Eribaxaban
Idraparinux (SQ)
LY517717
YM150
TAK-442
IXa
Xa
II
Direct Thrombin
Inhibitors
IIa
Fibrinogen
Factor Xa
Inhibitors
Fibrin
Ximelagatran
Dabigatran
AZD-0837
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
Approved Dosage Forms
10, 15, & 20 mg tablets
Nonvalvular Atrial Fibrillation Dosing
Normal Renal Function
(CrCl > 50 ml/min)
20 mg once daily*
Moderate Renal Impairment
(CrCl 15 – 50 ml/min)
15 mg once daily*
Severe Renal Impairment
(CrCl < 15 ml/min)
Avoid use
Prophylaxis of DVT
10 mg once daily with or without food
*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 AF
Outcomes
Rivaroxaban
(n=7081)
Warfarin
(n=7090)
Hazard Ratio
(95% CI)
P-value
Stroke or systemic
embolic event
(non-inferiority)
1.71
2.16
0.79 (0.66-0.96)
<0.001
Stroke or systemic
embolic event
(superiority)
1.70
2.15
0.79 (0.65-0.95)
0.015
Stroke or systemic
embolic event
(ITT superiority)
2.12
2.42
0.88 (0.74-1.03)
0.117
Major bleeding
3.60
3.45
1.04 (0.90-1.20)
0.576
Major and clinically
relevant bleeding
14.91
14.52
1.03 (0.96-1.11)
0.442
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 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 51
Rivaroxaban
2.5 mg
(n=5114)
Rivaroxaban
5 mg
(n=5115)
Placebo
(n=5113)
P-value
(combined)
TIMI major
bleeding
1.8
2.4
0.6
<0.001
TIMI minor
bleeding
0.9
1.6
0.5
0.003
Bleeding requiring
medical attention
12.9
16.2
7.5
<0.001
Intracranial bleed
0.4
0.7
0.2
0.009
Safety
• 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
www.clinicaltrials.gov accessed 3/2012
Rivaroxaban Prior to PCI
• Half-life 5-9 hours; once daily dosing
• Activity does not correlate with aPTT or ACT
Procedural Bleed Risk
Standard Risk
High Risk
Hold for 24 hours
Hold for 24-48 hours
*Consider longer drug free interval in renal impairment
Rivaroxaban Post Procedure
Resume Rivaroxaban
Standard Risk
High Risk
24 hours post
48 hours post
• 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
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
• 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
ARISTOTLE
Apixaban
(n=9120)
Warfarin
(n=9081)
Hazard
Ratio
P-value
Stroke or systemic
embolic event
1.27
1.6
0.79
0.01
Death from any cause
3.52
3.94
0.89
0.047
Major bleeding
2.13
3.09
0.69
<0.001
Any bleeding
18.1
25.8
0.71
<0.001
Stroke, systemic
embolism, major bleed
3.17
4.11
0.77
<0.001
Outcomes
• 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-2
Apixaban
(n=3705)
Placebo
(n=3687)
Hazard Ratio
P-value
CV death, MI, stroke
7.5
7.9
0.95
0.51
TIMI major bleeding
1.3
0.5
2.59
0.001
GUSTO major
bleeding
1.0
0.3
3.05
0.001
Intracranial bleed
0.3
0.1
4.06
0.03
CV death, MI, stroke,
fatal bleeding
8.0
8.1
0.98
0.80
Outcomes
• 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
Choice of Agent
Atrial Fibrillation Trial Comparison
Variables
RE-LY
(n=18,113)
ROCKET-AF
(n=14,264)
ARISTOTLE
(n=18,201)
Study drug
Dabigatran
150 mg BID
Rivaroxaban
20 mg daily
Apixaban
5 mg BID
Comparator
Warfarin INR 2-3
Warfarin INR 2-3
Warfarin INR 2-3
TTR (mean)
64%
55%
62.2%
Mean Age
71 yo
73 yo
70 yo
CHADS2 score
2.2
3.5
2.1
Primary
Outcome
1.11% vs. 1.69%
(p<0.001)
2.12% vs. 2.42%
(p=0.117)
1.27% vs. 1.6%
(p<0.001)
Major bleeding
3.11% vs. 3.36%
(p=0.31)
3.60% vs. 3.46%
(p=0.576)
2.13% vs. 3.09%
(p<0.001)
Characteristics of Novel Agents
Variables
Dabigatran
Rivaroxaban
Apixaban
FDA approved
October 2010
November 2011
N/A
Drug Class
DTI
Factor Xa Inhibitor
Factor Xa Inhibitor
Tmax (hrs)
1-3
2-4
1-3
Half-life (hrs)
14-17
5-9
8-15
Dose Interval
Twice daily
Once daily
Twice daily
Renal
80%
36%
25%
Renal Dose Adj.
Yes
Yes
Unlikely
Hepatic Impairment
No adjustment
Avoid Use
Caution / Avoid Use
Other AEs
Dyspepsia
N/A
N/A
Possible Monitoring
pTT, ACT
PT, anti-Xa
PT, anti-Xa
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
Bleeding on Therapy
Mild
Delay next dose
or discontinue
Thromb Haemost 2010;103:1116-1127
Moderate-Severe
Life-Threatening
Symptomatic Treatment
Compression
Surgical intervention
Fluid replacement
Blood transfusion
Charcoal (overdose)
Dialysis (dabigatran)
Consider rFVIIa
or PCC
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
Pharmacotherapy 2011;31(12):1175-91
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
• 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
• 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?