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Transcript
New Anticoagulants For Stroke
Prevention in AF
Gerald V. Naccarelli M.D.
Consultant: Glaxo-Smith-Kline, Pfizer, Sanofi, BoehringerIngelheim, Bristol Myers Squibb, Otsuka, Forest, Janssen,
Daiichi-Sankyo
Atrial Fibrillation and Stroke
● Stroke is the most common complication of AF1,2
– Incidence of all-cause stroke in AF patients is 5%1
– Approximately 15% of all strokes in the U.S. are
caused by AF1 (75,000 strokes per year)
– 90% of strokes in NVAF are ischemic
– Elderly ( > 75 y.o.) AF pts (No AC) have a 5.49
increased risk of ischemic stroke vs. < 65 y.o.3
– Annualized stroke rate is 3.2% in paroxysmal and
3.3% in persistent AF
● Ischemic stroke associated with AF is often more severe
than stroke from other etiology4
● Stroke risk persists even in asymptomatic AF5
● In AF patients <70 years old: 187% greater risk of
dementia and 130% increased risk for Alzheimer's6
)
1) Fuster V, et al. J Am Coll Cardiol. 2006;48:854-906 ; 2. Benjamin EJ, et al. Circulation. 1998;98:946-9523.
3) Friberg L, et al. Eur Heart J 2012; 33:1500-1510; 4) Dulli DA, et al. Neuroepidemiology. 2003;22:118-123;
5) Page RL, et al. Circulation. 2003;107:1141-1145; 6) Bunch. Heart Rhythm Society-. Boston, MA., 2009.
Stroke Risk Stratification in AF
Annual Risk of Stroke (%)
CHADS2
Risk Factor
Cardiac failure
HTN
Age ≥75 years
Diabetes
Stroke
Score
1
1
1
1
2
CHA2DS2-VASc
Risk Factor
Score
Cardiac failure
1
HTN
1
Age ≥75 years
2
Diabetes
1
Stroke
2
Vascular disease (MI, peripheral
1
arterial disease, aortic atherosclerosis)
Age 65-74 years
1
Sex category (female)
1
HTN = hypertension; MI = myocardial infarction.
Lip GY, et al. Am J Med. 2010;123(6):484-488.
20
18
CHADS2
16
CHA2DS2-VASc
14
12
10
8
6
4
2
0
0
1
2
3
4
5
6
7
8
9
Total Score
Camm AJ, et al. Eur Heart J. 2010:31;2369-2429.
1
ACCP 2012 AF Guidelines
Antithrombotic therapy recommendations to prevent stroke
Risk
Category
CHADS2 Score
Low Risk
0
Moderate Risk
1
High Risk
≥2
Recommended Therapy
No therapy
If therapy, preferred:
Aspirin over OAC* or
combination of aspirin and
clopidogrel
OAC*
Preferred: OAC* over
aspirin or combination of
aspirin and clopidogrel
OAC*
*Dabigatran 150mg twice daily preferred over a vitamin K antagonist.
ACCP = American College of Chest Physicians; OAC = Oral anticoagulant.
You JJ, et al. Chest. 2012;141:e531S-75S.
ESC Focused AF Guideline Update
● The efficacy of stroke prevention with aspirin is weak, with a
potential of harm, since the risk of major bleeding (and ICH)
with aspirin is not significantly different to that of OAC,
especially in the elderly
● The use of antiplatelet therapy (as aspirin-clopidogrel
combination therapy or - less effectively - aspirin
monotherapy for those who cannot tolerate aspirinclopidogrel combination therapy) for stroke prevention in AF
should be limited to the few patients who refuse any form of
OAC
● The CHA2DS2-VASc score is better at identifying “truly low
risk” patients with AF and as good as – and possibly better
than – scores such as CHADS2 in identifying patients who
develop stroke and thromboembolism
Camm AJ, et al. Eur Heart J 2012
ESC Focused AF Guideline Update
● The NOACs offer better efficacy, safety, and
convenience compared with OACS with VKAs. Thus,
where and OAC is recommended, one of the NOACs
– either a direct thrombin inhibitor (dabigatran) or an
active factor Xa inhibitor (e.g. rivaroxaban, apixaban)
– should be considered instead of adjusted-dose VKA
( INR 2-3) for most patients with AF
● There is insufficient evidence to recommend one
NOAC over another, although some patient
characteristics, drug compliance and tolerability, and
cost may be important considerations in the choice of
agent
Camm AJ, et al. Eur Heart J 2012
2
Mechanism of Action of Warfarin
Steps in Coagulation
Coagulation Cascade
Drug
TF/VIIa
Initiation
X
IX
VIIIa
Va
Xa
Propagation
IXa
Warfarin
II
Thrombin (IIa)
Thrombin
Activity
Fibrinogen
Fibrin
Adapted with permission from Weitz JI, et al. Chest. 2004;126:265S-286S.
Weitz JI, et al. Chest. 2004;126:265S-286S.
Hirsh J, et al. Circulation. 2003;107:1692-1711.
Efficacy of Warfarin
Compared With Control in 5 Studies
62% to 67% RRR with warfarin vs placebo
No. of PatientEvents Years
AFASAK
27
Risk Reduction, %
811
BAATAF
15
922
CAFA
14
478
SPAF
23
508
SPINAF
29
972
Combined
108
3691
100
50
0
Warfarin Better
-50
-100
Warfarin Worse
Atrial Fibrillation Investigators. Arch Intern Med. 1994;154(13):1449-1457.
Warfarin for Nonvalvular AF
Pooled data from AFASAK, SPAF, and BAATAF
For every 1000 patients with nonvalvular AF in clinical trials
treated with warfarin for 1 year:
Benefit
Risk
31 fewer thromboembolic events*
1 more intracranial or major bleed*
*Compared with control
35 more minor bleeds occurred with
warfarin Intention-to-treat analysis
Risk of ICH increases with age
Adapted from Albers GW et al. Ann Neurol. 1991;30:511-8.
3
Therapeutic Range for Warfarin:
Balancing Safety and Efficacy
Odds Ratio
15.0
Stroke
10.0
Intracranial Bleeding
Therapeutic Range
5.0
1.0
0
1.0
2.0
3.0
5.0
4.0
6.0
7.0
8.0
INR
Hylek EM, Singer DE. Ann Intern Med. 1994;120(11):897-902.
Hylek EM, et al. N Engl J Med. 2003;349(11):1019-1026.
Warfarin Use: Medicare Cohort
% Taking Warfarin
60
50
40
30
20
10
0
1992
1994
1996
1998
2000
2002
Year
Adapted from Lakshminarayan K, et al. Stroke. 2006;37(8):1969-1974.
TTR Was 55% in a Systematic
Overview of US Centers
Setting
TTR (95% CI)
Anticoagulation
clinic-based
warfarin dosing
0.63 (0.58,0.68)
Community-based
warfarin dosing
0.51 (0.47,0.55)
Overall
0.55 (0.51,0.58)
0.2
0.5
1.0
TTR (95% CI)
● Analysis of 8 studies with >41,000 patient years of total follow-up
● Anticoagulation clinic services are associated with improved TTR
Abbreviations: TTR = time in therapeutic range; CI = confidence interval.
Adapted from Baker W et al. J Manag Care Pharm. 2009;15(3):244-252.
4
INR Control and Outcomes in AF
Cumulative Survival
● 486 AF patients with CHADS2 ≥2 on warfarin
● Mean duration of treatment, 986 days; mean of 66 INRs
● Compared with no warfarin, stroke was significantly reduced only in
patients with TTR >70%
1.0
TTR
0.9
71–100%
61–70%
51–60%
41–50 %
31–40 %
<30%
Non-warfarin
0.8
0.7
0.6
0
500
1000
1500
Survival to Stroke (days)
TTR, time in therapeutic range.
Morgan CL, et al. Thromb Res. 2009;124(1):37-41.
The Challenges of Using Warfarin
– The intensity of AC achieved through the use of warfarin is affected by a
number of genetic, environmental, and patient factors
 Interacting
medication
(eg, NSAIDs, ASA)
Drug-related
 Dietary
vitamin K intake
 Herbal
supplements
 Alcohol
 Inability to adhere to restrictions
(dietary, drug, alcohol, etc)
 Poor compliance with medication
 Dosing errors
 Discomfort or inconvenience of
frequent venipuncture
 Age
Patient
 Genetic
medical
(CYP2C9, VKORC1)
characteristics  Acute
Warfarin
management




diarrheal illness
Renal impairment
Hepatic dysfunction
Impaired GI absorption
Malignancy
Patient
capabilities
or preference
ASA=aspirin; CYP2C9=cytochrome P450 2C9; GI=gastrointestinal; NSAIDs=nonsteroidal antiinflammatory drugs; VKORC1=vitamin K epoxide
reductase complex, subunit 1.
Merli GJ, Tzanis G. J Thromb Thrombolysis. 2009;27(3):293-299.
Aspirin Has Minimal Efficacy in
Preventing CVA in AF
Aspirin vs Placebo
Relative Risk Reduction (95% CI)
AFASAK I
SPAF I
EAFT
ESPS II
LASAF
UK-TIA
All Trials (N=6)
100%
50%
Aspirin Better
0%
–50%
–100%
Aspirin Worse
Hart RG, et al. Ann Intern Med. 1999;131(7):492-501.
5
Antiplatelet Therapy in AF
ACTIVE-W:
6706 randomized patients;
trial stopped
ACTIVE-A:
7554 randomized patients;
median follow-up of 3.6 years
8
P = .0003
5
4
P = .001
3
P = .53
2
Clopidogrel + ASA
ASA
6
5
4
P<.001
3
P<.001
2
1
1
0
P = .01
7
Outcome/Year (%)
Outcome/Year (%)
6
Clopidogrel + ASA
Warfarin
Vascular
Event
Stroke
0
Major
Bleeding
Vascular
Event
Stroke
Major
Bleeding
ACTIVE = AF Clopidogrel Trial with Irbesartan for Prevention of Vascular Events.
ACTIVE Investigators. Lancet. 2006;367:1903-1912. ACTIVE Investigators. N Engl J Med.
2009;360(20):2066-2078.
Sites of Action for the
New Anticoagulants
Intrinsic
XII
Extrinsic
XI
TF
IX
VII
VIII
X
V
Thrombin IIa
Fibrinogen
Xa Inhibitors
– Apixaban
– Edoxaban*
– Rivaroxaban
Direct Thrombin
Inhibitor
– Dabigatran
Fibrin Clot
*Not currently FDA approved.
Weitz JI, et al. Chest 2001;119:95S-107S. Gulseth MP, et al. Am J Health Syst Pharm 2008;65:1520-1529.
New Oral Anticoagulants
Drug
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Mechanism of Thrombin
inhibitor
action
FXa inhibitor
FXa inhibitor
FXa inhibitor
Half-life
14-17 h
6-9 h
12 h
6-12 h
Regimen
BID
QD, BID
BID
QD
Peak to
trough
~7x
12x (QD)
3-5x
~3x
Renal
excretion
~80%
36-45%
25-30%
35%
CYP3A4
substrate and Pglycoprotein
inhibitor
CYP3A4
substrate(min)
P-glycoprotein
inhibitor
Potential drug P-glycoprotein
inhibitor
interactions
CYP3A4
substrate and Pglycoprotein
inhibitor
Usman MH, et al. Curr Treat Cardiovasc Med. 2008;10(5):388-397.
Piccini JP, et al. Curr Opin Cardiol. 2010;25(4):312-320.
6
Heidbuchel H, et al. Europace 2013;15:625-651
Restricted Use of Dabigatran,
Rivaroxaban and Apixaban
● Renal impairment
● Pregnancy Category C: No adequate and wellcontrolled studies
● Labor and delivery
● Nursing mothers
● Pediatric use
● Prosthetic Heart Valves
RE-ALIGN trial stopped due to more thromboembolic and bleeding events
with dabigatran in bi-leaflet mechanical prosthetic heart valves
Dabigatran
●
●
●
●
●
●
●
●
●
Potent, competitive, reversible inhibitor of thrombin
Binds clot-bound and free thrombin (high affinity/ specificity)
Bioavailability 6.5%; low protein binding
No known food or CYP450 drug interactions
– Decreased absorption with H2 blockers/PPIs
Decreased levels with PGP inducers (rifampin) and
increased levels with PGP inhibitors (verapamil,
amiodarone, dronedarone)
Dyspepsia most common subjective adverse effect
No need for INR monitoring
Half-life: 8 hours after single dose and 14-17 hours after
multiple doses with BID dosing
80% renal excreted
7
RE-LY® – PROBE Study Design
Non-valvular atrial fibrillation at moderate
to high risk of stroke or systemic embolism
(at least one additional risk factor) (N=18,113)
R
Warfarin
1 mg, 3 mg, 5 mg
(INR 2.0-3.0)
N=6022
●
●
●
●
Dabigatran Etexilate
110 mg bid
N=6015
Mean CHADS2 = 2.1
Median TTR = 67%
Dabigatran Etexilate
150 mg bid
N=6076
Primary objective: Non-inferiority to warfarin
Minimum 1 year follow-up, maximum of 3 years; mean 2 years
Primary end point: Stroke + systemic embolism
Primary safety outcome: Incidence of major bleeds
Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-1151
NOAC Trials: Key Exclusion Criteria
● RELY
– Mechanical prosthetic valve or hemodynamically
significant valve disease
– CrCl < 30 ml/min
● ROCKET AF
– Hemodynamically significant MS or any valve prosthesis
– CrCl < 30 ml/min
● ARISTOTLE
– Moderate or severe MS or prosthetic valve
– Cr >2.5 or CrCl <25 ml/min
● ENGAGE AF (TIMI 48)
– Moderate or severe mitral stenosis, unresected atrial
myxoma, or a mechanical heart valve
– CrCl < 30 ml/min
All patients had to be candidates for warfarin and low dose ASA allowed in all trials
RE-LY Trial
Dabigatran vs. Warfarin
18,113 patients with nonvalvular AF randomized to warfarin (goal INR 2-3),
dabigatran (150 mg BID), or dabigatran (110 mg BID) for a median of 2 years
P=0.051
4.0
P=0.32
3.5
Warfarin INR 2.03.0
Percent/Year
3.0
2.5
2.0
1.5
Dabigatran
150 mg twice daily
TTR=67%
Superiority P<0.001
Noninferiority P<0.001
P<0.001
P=0.03
P<0.001
1.0
P<0.001
0.5
0.0
Stroke or Ischemic HemorrhagicAll Cause
Stroke
Systemic
Mortality
Stroke
Embolism
Major Intracranial Major GI
Bleed Hemorrhage Bleed
P-values are for superiority. The 110 mg twice daily is not presented as this dose was not approved by the FDA.
AF = Atrial fibrillation; FDA = US Food and Drug Administration; GI = Gastrointestinal; MI = Myocardial infarction;
TTR = Time in therapeutic range.
Connolly SJ, et al. N Engl J Med 2009;361:1139-1151. Connolly SJ, et al. N Engl J Med 2010;363:1875-1876.
8
Dabigatran: Recommended Dosing
Creatinine Clearance
>30 mL/min
15-30 mL/min
<15 mL/min or dialysis
Dabigatran Dose
150 mg twice daily
75 mg twice daily
contraindicated
• Avoid use with PgP inducers (rifampin)
• If CrCl 30-50 and dronedarone – consider 75 mg bid
ROCKET AF Enrolled Patients With Nonvalvular AF
at Moderate to High Risk of Stroke
Nonvalvular AF
Mean CHADS2 score = 3.5
Randomized
double-blind/
double-dummy
(N=14,264)2
CHADS2 Risk Factors
• Prior stroke, TIA, or non-CNS
systemic embolus
– OR –
• CHF or LVEF ≤35%
At least 2
• Hypertension
required
• Age ≥75 years
• Diabetes
Warfarin
Rivaroxaban
20 mg/d
(15 mg/d for CrCl 30 to <50 mL/min)1,2
INR target:
2.0 to 3.0 inclusive
Monthly assessments*
Warfarin management was determined by clinician1,2
Mean CHADS2 = 3.5
Median TTR for the warfarin arm was 58%
Patel MR et al. N Engl J Med. 2011;365(10):883-891.
ROCKET AF Study Investigators. Am Heart J. 2010;159(3):340-347.
Rivaroxaban: Pharmacologic Profile
● Oral, once-daily dosing
● Predictable pharmacokinetics
and pharmacodynamics1,2
● Rapid onset
–
1/3 Unmetabolized
Direct Renal Excretion
2/3 Metabolized
in Liver
Cmax of 2 to 4 hours
– Maximum inhibition of Factor Xa activity
at 1-4 hours after administration3*
● Dual mode of clearance1
– 1/3 direct renal excretion
– 2/3 metabolized in the liver
● T1/2 of 5 to 9 hours in healthy individuals
aged 20 to 45 years
– T1/2 11 to 13 hours in the elderly
1/2 excreted
via the bile
1/2 excreted
via renal
elimination
● No requirement for routine coagulation
monitoring4,5
Abbreviations: T1/2 = half-life.
*Phase I randomized single-blind dose escalation study in 108 healthy white males aged 19 to 45 years. Single doses of rivaroxaban
1.25, 5, 10, 15, 20, 30, 40, 60, and 80 mg tablets were tested.
1. Perzborn E et al. Nat Rev Drug Discov. 2011;10(1):61-75. 2. Mueck W et al. Int J Clin Pharmacol Ther. 2007;45(6):335-344.
3. Kubitza D et al. Clin Pharmacol Ther. 2005;78(4):412-421. 4. Mueck W et al. Clin Pharmacokinet. 2008;47(3):203-216.
5. Patel MR 27
et al. N Engl J Med. 2011;365(10):883-891.
9
Inhibition of Factor Xa (%)
Rivaroxaban: Inhibition of Factor Xa Activity
over 24 hour Period
Anti-Factor Xa Activity
70
60
Rivaroxaban
Rivaroxaban
Rivaroxaban
Rivaroxaban
50
40
5 mg (n=6)
10 mg (n=8)
20 mg (n=7)
40 mg (n=8)
Placebo (n=25)
30
20
10
0
-10
0
2
4
6
8
10
12
14
16
18
20
22
24
Time (hours)
●
●
Results from a randomized, single-blinded, placebo-controlled, dose-escalation
study demonstrated that once-daily dosing regimens of rivaroxaban tablets above
5 mg resulted in Factor Xa inhibition through 24 hours*
Results provided foundation for once-daily dosing regimens for evaluation in
phase 3 programs
*Pharmacokinetics/pharmacodynamics do not imply clinical effectiveness.
Kubitza D et al. Clin Pharmacol Ther. 2005;78(4):412-421.
Rivaroxaban Clinical Development Program
(>60,000 Patients)
Indications
Randomized Patients;
vs Comparator
DVT prophylaxis after
knee or hip surgery
9011 patients;
vs enoxaparin
Approved
Stroke/systemic
embolism in patients with
nonvalvular AF1
14,264 patients
noninferiority;
vs warfarin
Approved
ACS secondary
prevention2
>15,000 patients in addition to
standard therapy
Investigational
VTE primary prevention
in medically ill patients3
~8000 patients;
vs enoxaparin
Investigational
VTE treatment and
secondary prevention4,5
>9000 patients;
vs enoxaparin and
warfarin/acenocoumarol
Approved
Study Program
Status
Abbreviations: ACS = acute coronary syndrome; AF = atrial fibrillation; DVT = deep vein thrombosis.
1. Patel MR et al. N Engl J Med. 2011;365(10):883-991. 2. Gibson CM et al. Am Heart J. 2011;161(5):815-821. 3. ClinicalTrials.gov.
http://clinicaltrials.gov/ct2/show/NCT00809965. Accessed September 14, 2011. 3. Cohen AT et al. LBCT IV Session 3015. ACC 60th
Annual Scientific Sessions. New Orleans; LA; April 2-5, 2011. 4. EINSTEIN Investigators. N Engl J Med. 2010;363(26): 2499-2510;
29
5. ClinicalTrials.gov.
http://clinicaltrials.gov/ct2/show/NCT00439777. Accessed September 26, 2011.
Events Occurring on Treatment and After Early
Discontinuation Were Counted in ROCKET AF*
Median follow-up=707 days1
Last dose
+2 days
Rivaroxaban
R
A
N
D
O
M
I
Z
E
Early discontinuation (23.7%)1
Open-label therapy1
Last dose
+2 days
Events counted
(N=575)1
Open-label therapy1
Early discontinuation (22.2%)1
Warfarin
Day 0
Last dose
+2 days
Last dose
+2 days
End-of-study site notification
 Open-label therapy included VKA, aspirin, or no therapy, per
discretion of treating physician2
*Included all randomized subjects followed for events during treatment or after premature discontinuation until end-of-study
site notification (N=14,171).2
1.
Patel MR et al. N Engl J Med. 2011;365(10):883-891.
2.
2. ROCKET AF Study Investigators. Am Heart J. 2010;159(3):340-347.
10
ROCKET AF Trial
Rivaroxaban vs. Warfarin
14,264 patients with nonvalvular AF randomized to warfarin (goal INR 2-3)
or rivaroxaban (15-20 mg daily) for a median of 1.6 years
4.0
3.5
Percent/Year
3.0
Rivaroxaban
15 or 20 mg BID
Hazard ratio 0.88
(95% CI 0.75 -1.03)
Non inferiority
P<.001
Superiority P=0.12
P<.001*
Warfarin
TTR=55%
P=0.07
2.5
2.0
P=0.58
P=0.58
1.5
P=.02*
1.0
*P=.024
0.5
0.0
Stroke or Ischemic Hemorrhagic All Cause
Systemic Stroke
Stroke
Mortality
Embolism
Major Intracranial Major GI
Bleed Hemorrhage Bleed
GI = Gastrointestinal, MI = Myocardial infarction; TTR = Time in therapeutic range.
Patel MR, et al. NEJM 2011;365:883-891.
The Importance of Adequate Anticoagulation
After Discontinuation of Rivaroxaban
Similar data for apixaban in ARISTOTLE
21
5
No. of Strokes
● Anticoagulation after
discontinuation was not stipulated
in ROCKET AF
● Warfarin patients who completed
the study were generally
maintained on warfarin
● Rivaroxaban patients were
generally switched to warfarin
– There was no co-administration of
warfarin and rivaroxaban
– This resulted in inadequate
anticoagulation after stopping
rivaroxaban until attaining a
therapeutic INR
Rivaroxaban
(n=4637)
Median time to
INR 2.0-3.0
Warfarin
(n=4691)
13 days
3 days
Patel MR et al. N Engl J Med. 2011;365(10):883-991.
Results in ROCKET AF Across Renal
Functions Studied
Favors
Rivaroxaban
n/N (%)
Rivaroxaban
Favors
Warfarin
Warfarin
Stroke/non–CNS embolism1
Overall
269/7081 (3.8)
306/7090 (4.3)
CrCl (mL/min)
<50
50-80
77/1490 (5.2)
86/1459 (5.9)
126/3298 (3.8)
151/3400 (4.4)
>80
65/2285 (2.8)
68/2222 (3.1)
Major and nonmajor clinically relevant bleeding2
Overall
1475/7111 (14.91) 1449/7125 (14.52)
CrCl (mL/min)
<50
336/1502 (17.84) 342/1476 (18.28)
50-80
725/3313 (15.74) 719/3410 (15.30)
>80
412/2288 (12.15) 388/2230 (11.42)
0.1 0.2
Patel MR et al. N Engl J Med. 2011;365(10):883-991.
0.5 1.0 2.0
5.0 10
HR
11
Rivaroxaban: Dosing
CrCl (mL/min)
Recommended
once-daily dose of Rivaroxaban
>50
20 mg
15 to 50
15 mg*
<15
Avoid use
♦ Should be taken once daily with the evening meal
♦ If a dose of is not taken at the scheduled time, administer the
dose as soon as possible on the same day
– Do not administer 2 doses on the same day
34 dose for patients with CrCl of 15 to <30 Ml/min is based on exposure matching.
*The 15-mg
Apixaban
● Oral, reversible, and selective active site inhibitor of
Factor Xa
● Bioavailability: 50% (no food effect)
● Maximum concentration 3-4 hours after dose
● Half-life: 12 hours
● Renal excretion: 27%
● Linear pharmacokinetics (if doses 25 mg or more –
dissolution limited absorption and bioavailability)
● Plasma Protein Binding: 87%
● Metabolized mainly via CYP3A4; no active
metabolites
● Apixaban is a substrate for P-gp transporter
The AVERROES (Apixaban Versus ASA To
Reduce the Risk Of Stroke) Trial
unsuitable for
warfarin therapy
N= 5,598
E
ASA (N=2791)
(81–324 mg daily; up to 36
months/end of study)
Mean duration of exposure
= 59 weeks
R Double-blind
Apixaban (N=2807)
(5 mg twice daily; 2.5 mg in
selected patients*; up to 36
months/end of study)
*At least two of: age
80 y; weight 60 kg;
or serum Cr 1.5 mg/dl
Is apixaban more effective than ASA in preventing stroke and systemic embolism in moderate to high-risk
(stroke; at least one risk factor) AF patients?
10 efficacy endpoint: confirmed ischemic or haemorrhagic stroke or systemic embolism
20 study endpoints: as above, including MI or vascular death
10 safety endpoint: major bleeding
Study period: until 226 primary outcome events have been observed; estimated 1o completion May 2010
In June 2010, BMS- Pfizer announced that the study had been stopped early because a predefined interim
analysis revealed clear evidence of a clinically important reduction in stroke and systemic embolism.
Eikelboom, et al. Am Heart J 2010;159:348-353; ClinicalTrials.gov identifier: NCT00496769;
Connolly SJ, et al. N Engl J Med 2011;364:806-817
12
AVERROES:
Stroke or Systemic Embolic Event
RR=0.45
95% CI, 0.32-0.62
P<0.001
Cumulative Risk
0.05
ASA
0.03
Apixaban
0.01
0.0
0
3
6
9
12
18
21
Months
Connolly SJ, et al. N Engl J Med 2011; 364:806-817
AVERROES: Primary Outcome Events
Apixaban
ASA
Apixaban vs. ASA
Annual
Annual
events
events
RR
rate
rate
Outcome
95% CI
P
Stroke or SEE
52
1.6
112
3.6
0.46 0.33-0.64 <0.001
Stroke
50
1.5
103
3.3
0.48 0.34-0.68 <0.001
Ischemic
35
1.1
92
2.9
0.38 0.26-0.56 <0.001
Hemorrhagic
8
0.2
8
0.2
1.01 0.38-2.68
0.99
Type not
determined
8
0.2
4
0.1
1.99 0.60-6.62
0.26
2
<0.1
13
0.4
0.15 0.03-0.69
0.01
SEE
38
30
Connolly SJ, et al. N Engl J Med 2011; 364: 806-817
AVERROES: Major Bleeding
RR=1.13
95% CI, 0.74-1.75
P=.56
0.020
Apixaban
Cumulative Risk
0.015
ASA
0.010
0.005
0.0
0
3
6
9
12
18
21
Months
Connolly SJ, et al. N Engl J Med 2011; 364:806-817
13
The ARISTOTLE Trial: Apixaban
ClinicalTrials.gov identifier: NCT00412984
Warfarin INR 2.0–3.0 (N=9081)
AF or atrial flutter
18,201 randomized
E
Mean duration of exposure
= 89 weeks
R Double-blind
*At least two of: age
 80 years; weight  60 kg;
or serum Cr  1.5 mg/dL
Apixaban (N=9120)
(5 mg twice daily; 2.5 mg twice
daily in selected patients*)
Is apixaban non-inferior to standard therapy (warfarin) in preventing stroke and systemic
embolism in moderate to high-risk (stroke; at least one risk factor) AF patients?
10 efficacy endpoint: confirmed ischemic or hemorrhagic stroke, or systemic embolism
20 efficacy endpoints: composite of confirmed ischemic or haemorrhagic stroke, systemic
embolism and all-cause death
10 safety endpoint: time to first occurrence of confirmed major bleeding
Mean CHADS2 = 2.1
Median TTR = 66%
Lopes, et al. Am Heart J 2010;159:331–339; Granger CB, et al. N Engl J Med. 2011; 365:981-992.
ARISTOTLE Trial
Apixaban vs. Warfarin
18,201 patients with AF+ ≥1: TIA/CVA/embolism, ≥75 years,
History CHF or LVEF ≤40, HTN, DM
P=0.047
4.0
Apixaban = 9120
3.5
P<0.001
Warfarin = 9081
Percent/Year
3.0
2.5
2.0
1.5
1.0
Non inferiority
P<0.001
Superiority P<0.01
TTR = 66%
P=0.42
P=0.37
P<0.001
P=0.001
0.5
0.0
Stroke or Ischemic HemorrhagicAll Cause
Systemic
Stroke
Stroke Mortality
Embolism
Major Intracranial Major GI
Bleed Hemorrhage Bleed
GI = Gastrointestinal, MI = Myocardial infarction; TTR = Time in therapeutic range.
Granger CB, et al. N Engl J Med. 2011;365(11):981-992.
Apixaban: Dosing
• Dosing: 5 mg bid with or without food
• Recommended dose is 2.5 mg bid in patients with any 2
of the following characteristics:
•
age ≥ 80 years
•
body weight ≤60 kg
•
serum creatinine ≥1.5 mg/dL
• When apixaban is co-administered with strong dual inhibitors of
cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp)
(increases blood levels of apixaban), the recommended dose is 2.5
mg twice daily.
• If already on 2.5 mg dose – avoid or do not use apixaban
•
Avoid concomitant use of apixaban with drugs that are
strong dual inducers of cytochrome P450 3A4 (CYP3A4)
and P-glycoprotein (P-gp) (decreases blood levels of apixaban)
14
ENGAGE AF TIMI 48: Edoxaban
Warfarin INR 2.0–3.0
AF
>20,000 pts
3 treatment arms
E
R Double-blind
Edoxaban
(60 mg vs. 30 mg qd)
Is edoxaban non-inferior to standard therapy (warfarin) in preventing stroke and systemic
embolism in moderate to high-risk (CHADS2 score > 2) AF patients?
10 efficacy endpoint: composite primary endpoint of stroke and systemic embolic events
20 efficacy endpoints: composite clinical outcome of stroke, systemic embolic events, and allcause mortality; also major bleeding events.
50% dose reductions occurred for one or more of the following:
CrCl 30-50 mL/min; Body weight ≤60 kg; Concomitant strong P-gp inhibitors
Treatment period: up to 2 years; results expected 2013
Ruff et al. Am Heart J 2010;160:635-641
ClinicalTrials.gov identifier: NCT00412984.
Dabigatran as P-glycoprotein Substrate
P-glycoprotein
Dabigatran
Efflux transporter
X
Dabigatran
etexilate
Dabigatran
etexilate
Dabigatran
etexilate
Rivaroxaban, Apixaban,
Edoxaban
also PgP substrates
• P-gp inducers (rifampin, St. John’s Wort)
– Reduce exposure to NOACS by
– 33-65% and should be avoided
absorption
Bloodstream
Intestinal
lumen
Gut
wall
X
amiodarone, dronedarone,
verapamil blockade of P-gp
Drug – Drug Interactions
● Apixaban: Metabolized by CYP 3A4 and substrate of Pglycoprotein
– Decrease dose to 2.5 mg twice daily in patients taking strong
dual inhibitors of CYP 3A4 and P-glycoprotein (e.g.,
ketoconazole, itraconazole, ritonavir, clarithromycin)
– Avoid coadministration of strong dual inhibitors of CYP 3A4 and
P-glycoprotein in patients already taking 2.5 mg twice daily
– Avoid coadministration with strong dual inducers of CYP3A4 and
P-gp (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort:
will decrease apixaban exposure).
Food and Drug Administration. [email protected] – Apixaban.
Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
15
Drug – Drug Interactions
Continued
● Dabigatran: Metabolized by P-glycoprotein
– Decrease the dose to 75 mg twice daily if coadministered with a Pglycoprotein inhibitor (e.g., dronedarone, ketoconazole) and the
CrCl is 30-50 ml/min
– Avoid if coadministered with a P-glycoprotein inhibitor (e.g.,
dronedarone, systemic ketoconazole) and the CrCl is <30 ml/min
– Avoid in conjunction with P-glycoprotein inducers (e.g., rifampin)
● Rivaroxaban: Metabolized by P-glycoprotein and CYP3A4
– Avoid in conjunction with P-glycoprotein and strong CYP3A4
inhibitors (e.g., ketoconazole, itraconazole, ritonavir, etc.)
– Avoid in conjunction with P-glycoprotein and strong CYP3A4
inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort)
Food and Drug Administration. [email protected] – Dabigatran or Rivaroxaban.
Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
20
Dabigatran plasma concentration
ECT ratio
INR
aPTT ratio
150
4
TT ratio
3
100
2
50
1
0
0
4
8
12
16
20
16
12
8
TT (ratio)
200
INR and aPTT, ECT (ratio)
Dabigatran Plasma Concentration (ng/mL)
Dabigatran Plasma Concentrations
Parallel Its Anticoagulant Effect
4
0
24
Time (h)
aPTT= activated partial thromboplastin time, ECT= ecarin clotting time, INR= international normalized ratio, TT= thrombin time.
Stangier J et al. Br J Clin Pharmacol. 2007;64:292-303.
Monitoring Anticoagulation
● Normally there is NO indication for anticoagulation
monitoring of new agents
● Agents can prolong various clotting tests
– DO NOT provide a reliable and accurate prediction of a
patient’s coagulation status
● Apixaban:
– Prolongs clotting tests: prothrombin time (PT), INR and activated
partial thromboplastin time (aPTT)
– Not recommended to monitor anticoagulation effect of apixaban
– Rotachrom FXa assay is a test where the activity correlates well
with drug levels of apixaban.
aPTT = Activated partial thromboplastin time; INR = International Normalization Ratio.
Food and Drug Administration. [email protected] - Apixaban.
Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Barrett Y, et al. Thrombosis and Haemostasis. 2010;104(6):1263–1271.
16
Monitoring Anticoagulation
Continued
● Dabigatran:
– Coagulation status can be assessed using the aPTT, ECT, and
TT
– INR cannot be interpreted in the same way as with warfarin
– aPTT is the most widely available test with a level of 40 seconds
corresponding to the lowest 10th percentile in the RE-LY trial
● Rivaroxaban:
– Coagulation status can be assessed using the PT/INR, aPTT,
HepTest, and Anti-factor Xa activity
– Among the more widely available tests, the PT/INR is more
sensitive than the aPTT
aPTT = Activated partial thromboplastin time; ECT = Ecarin clotting time; TT = Thrombin time.
Food and Drug Administration. [email protected] – Dabigatran or Rivaroxaban
Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Switching Patients From
Warfarin to NOACs
● Dabigatran – stop warfarin and start
dabigatran when INR < 2.0
● Rivaroxaban – stop warfarin and start
rivaroxaban when INR < 3.0
● Apixaban – stop warfarin and start
apixaban when INR < 2.0
To switch from one NOAC to another consider just
substituting new drug at next dose
Periprocedural Management of
New Anticoagulants
● Apixaban:
– Stop ≥ 48-hrs before elective surgery or invasive procedures with
moderate or high risk of significant bleeding
– Stop ≥ 24 hrs before elective surgery or procedures with low bleeding
risk
● Dabigatran:
– Stop 1-2 days (CrCl ≥ 50 mL/min) or 3-5 days (CrCl < 50 mL/min)
before elective surgery or invasive procedures
● Rivaroxaban:
– Stop ≥ 24 hours before elective surgery or invasive procedures
– Bridging therapy not usually required
– Consider longer discontinuation times (≥5-7 days) in patients
undergoing major surgery, spinal puncture, or placement of a spinal or
epidural catheter or port, in whom complete hemostasis may be
required
Food and Drug Administration. [email protected] – Apixaban or Dabigatran or Rivaroxaban.
Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
17
NOACs: Reversing
Anticoagulation Effects
 There is no established way to reverse the anticoagulant effect of





NOACs; some of the anticoagulant effect can be expected to persist for
24-48 hours after the last dose (relevant for bridging for procedures)
Specific antidote for NOACs not available
Dabigatran is dialyzable, because of high plasma protein binding,
apixaban and rivaroxaban are not dialyzable
Protamine sulfate and vitamin K, hemostatics or antifibrinolytic agents
would not be expected to affect the anticoagulant activity of NOACs
Use of procoagulant reversal agents such as prothrombin complex
concentrate, activated prothrombin complex concentrate, or
recombinant factor VIIa may be considered but has not been evaluated
carefully in clinical studies
Activated oral charcoal reduces absorption apixaban, thereby lowering
plasma concentrations. This approach may be useful with dabigatran
and rivaroxaban
NOACs: DC Cardioversion
N (Patients/CV)
CVA/SEE
Dabigatran 110 mg
409/647
5 (0.8%)
Dabigatran 150 mg
415/672
2 (0.3%)
Warfarin
431/664
4 (0.6%)
Apixaban
Warfarin
/338
/419
0 (0%)
0 (0%)
143
143
3 (2.1%)
3 (2.1%)
Rivaroxaban*
Warfarin
Nagarakanti R, et al. Circulation 2011;123:131-136
Flaker G, et al. ESC 2012
Piccini JP, et al. AHA 2012.
*ARC study in progress
SPAF: Novel Anticoagulants
“Unanswered Questions”
● Best dose of dabigatran if CrCl 30-49 ml/min
● Safety and best protocol for all drugs peri- AF ablation
– VENTURE-AF (Rivaroxaban) in progress
● Best measures of therapeutic anticoagulation
● Reversal agents
● Except for rivaroxaban – FDA approved doses for
other indications not well established
● Use in mechanical prosthetic valves – proper dose??
● Reasons for higher GI bleed and lower ICH
18
Summary: Novel Anticoagulants in AF
● Based on efficacy, safety, ease of use, new oral direct
thrombin inhibitors and factor Xa inhibitor drugs will
replace warfarin for many/most patients with AF
● Novel anticoagulants have a lower rate of ICH compared
to warfarin
● Dose adjustments need to be made based on renal
function
● Role in DC Cardioversion: Limited data – no data for any
of compounds that is concerning
● Safety/efficacy of novel anticoagulants for AF ablation
procedures still under study
● Need for antidote
19