Transcript Document

Clinical update – The big three
Michael D. Ezekowitz
Risk Reduction of Stroke Comparing
Warfarin With Placebo
Events (n) Patient-years
Risk reduction (%)
AFASAK: Peterson P, et al.
Lancet. 1989;1:175-179.
27
811
BAATAF Investigators.
N Engl J Med.
1990;323;1505-1511.
15
922
SPAF Investigators. Stroke.
1990;21:538-545.
23
508
SPINAF: Ezekowitz MD, et al.
N Engl J Med.
1992;327:1406-1412.
29
972
Combined
106
3,691
100
50
Warfarin
better
0
−50
−100
Warfarin
worse
Characteristics of New Oral
Anticoagulants
Drug
Dabigatran
Rivaroxaban
Apixaban
Betrixaban
Edoxaban
Inhibits
Thrombin
Factor Xa
Factor Xa
Factor Xa
Factor Xa
T1/2 (h)
14 – 17
5–9
12
19 – 24
6 – 12
Twice daily
Once or
twice daily
Twice daily
Once daily
Once daily
Peak:trough
2:1
12:1
(once daily)
3 – 5:1
≈ 3:1
≈ 3:1
Renal
excretion of
absorbed
drug (%)
≈ 80
35 – 45
25 – 30
≈ 15
35
P-gp inhibitor
CYP3A4
substrate
and P-gp
inhibitor
CYP3A4
substrate
and P-gp
inhibitor
Not substrate
for major
CYPs
CYP3A4
substrate
and P-gp
inhibitor
Regimen
Potential for
drug–drug
interactions
Usman MH, Ezekowitz MD. Curr Treat Cardiovasc Med. 2008;10:388-397.
Piccini JP, et al. Curr Opin Cardiol. 2010;25:312-320.
The Big Three: Comparing Study Design
Trial
Inclusion
Design
Duration
(median)
Enrollment
(N)
No.
sites
TTR (mean)
64%
RE–LY
ROCKET AF
ARISTOTLE
CHADS2 ≥ 1
(50% VKA naïve)
CHADS2 ≥ 2
(87% CHADS2 ≥ 3)
CHADS2 ≥ 1
(30% VKA naïve)
Openlabel
2y
(≈ 730 d)
18,113
951
67% warfarinexperienced
61% warfarinnaïve
Sham
INR
589 d
exposure,
707 d
including
period off
drug
during
follow-up
14,264
1,178
55%
Sham
INR
1.8 y
18,201
1,034
62%
Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2009;361:1139-1151; Patel MR, et al. N Engl
J Med. 2011;365:883-891; Granger CB, et al. N Engl J Med. 2011;365:981-992.
The Big Three: Comparing Patient Risk
Mean or
Median
(IQR)
patient
age (y)
Mean
CHADS2
score
CHADS2
≤ 1*
CHADS2
=2
71.5
2.1
≈ 32
ROCKET AF
73
(65 – 78)
3.5
ARISTOTLE
70
(63 – 76)
2.1
Trial
RE–LY
CHADS2
≥3
Prior
stroke /
TIA (%)
Warfarin
naïve (%)
≈ 35
≈ 33
≈ 20
≈ 50
0
13
87
≈ 55
≈ 38
34
36
30
≈ 20†
≈ 33
*RE–LY included patients with CHAD2 = 0 while ARISTOTLE did not
†Includes systemic embolism
Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2009;361:1139-1151; Patel MR, et al. N Engl
J Med. 2011;365:883-891; Granger CB, et al. N Engl J Med. 2011;365:981-992.
Statistical Methods: Efficacy
RE–LY
• Primary efficacy evaluation: Stroke or non-CNS embolism
– Non-inferiority: intention to treat
– Superiority: intention to treat
ROCKET AF
• Primary efficacy evaluation: Stroke or non-CNS embolism
– Non-inferiority: Protocol-compliant on treatment
– Superiority: On-treatment, then by intention to treat
ARISTOTLE
• Primary efficacy evaluation: Stroke or non-CNS embolism
– Non-inferiority: intention to treat
– Superiority: intention to treat
RE–LY AND ARISTOTLE used intention to treat for both non-inferiority and superiority testing;
ROCKET AF used on-treatment analysis for first tests of non-inferiority and superiority
Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2009;361:1139-1151; Patel MR, et al. N Engl
J Med. 2011;365:883-891; Granger CB, et al. N Engl J Med. 2011;365:981-992.
Statistical Methods: Safety
RE–LY
– Primary safety evaluation: major bleeding
ROCKET AF
– Primary safety evaluation: major or non-major
clinically relevant bleeding
ARISTOTLE
– Primary safety evaluation: major bleeding
Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2009;361:1139-1151; Patel MR, et al. N Engl
J Med. 2011;365:883-891; Granger CB, et al. N Engl J Med. 2011;365:981-992.
RE–LY
Dabigatran for Stroke Prevention in Atrial Fibrillation
Non-valvular AF at moderateto-high risk of stroke or systemic embolism
(at least 1 high-risk factor)
Warfarin
1 mg, 3 mg, 5 mg
(INR 2.0 – 3.0)
(n = 6,000)
Dabigatran etexilate
110 mg twice daily
(n = 6,000)
Dabigatran etexilate
150 mg twice daily
(n = 6,000)
• 1° objective: noninferiority to warfarin
• Minimum 1-year, maximum of 3 years, and mean of
2 years of follow-up
• 1° endpoint: stroke + systemic embolism
Ezekowitz MD, et al. Am Heart J. 2009;157:805-810.
RE–LY: Dabigatran 110 mg Twice Daily
Mean CHADS2 score = 2.1
Dabigatran better
Warfarin better
D110
W
P
—%/y—
Efficacy outcomes
Stroke / systemic embolism
1.54
1.71
0.30
Stroke
1.44
1.57
0.41
Ischemic stroke
1.34
1.20
0.35
Hemorrhagic stroke
0.12
0.38
< 0.001
Myocardial infarction
0.82
0.64
0.09
All-cause mortality
3.75
4.13
0.13
ICH
0.23
0.74
< 0.001
Major bleeding
2.87
3.57
0.003
Major GI bleeding
1.12
1.02
0.43
Any bleeding
14.62
18.15 < 0.001
Safety outcomes
0
0.5
1.0
Hazard ratio
1.5
Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2009;361:1139-1151.
Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2010;363:1875-1876.
2.0
RE–LY: Dabigatran 150 mg Twice Daily
Mean CHADS2 score = 2.1
Dabigatran better
Warfarin better
D150
W
P
—%/y—
Efficacy outcomes
Stroke / systemic embolism
1.11
1.71
< 0.001
Stroke
1.01
1.57
< 0.001
Ischemic stroke
0.92
1.20
0.03
Hemorrhagic stroke
0.10
0.38
< 0.001
Myocardial infarction
0.81
0.64
0.12
All-cause mortality
3.64
4.13
0.051
ICH
0.30
0.74
< 0.001
Major bleeding
3.32
3.57
0.32
Major GI bleeding
1.51
1.02
< 0.001
Any bleeding
16.42
18.15
0.002
Safety outcomes
0
0.5
1.0
Hazard ratio
1.5
Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2009;361:1139-1151.
Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2010;363:1875-1876.
2.0
RE–LY: Stroke and SE by
CHADS2 Score
D 110 mg vs.
warfarin
D 150 mg vs.
warfarin
Annual rate (%)
CHADS2
D 100
D 150
Warfarin
0–1
1.06
0.65
1.05
2
1.43
0.84
1.38
3–6
2.12
1.88
2.68
P = 0.44
0.50
1.0
Dabigatran 0
better
1.50
Warfarin
better
P = 0.82
0.50
1.00
Dabigatran
better
Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2009;361:1139-1151.
1.50
Warfarin
better
RE–LY: Major Bleeding by
CHADS2 Score
D 110 mg vs.
warfarin
D 150 mg vs.
warfarin
Annual rate (%)
CHADS2
D 100
D 150
Warfarin
0–1
1.81
1.96
2.70
2
2.71
2.80
3.14
3–6
3.62
4.64
4.28
P = 0.4
0.50
1.0
Dabigatran 0
better
1.50
Warfarin
better
P = 0.08
0.50
1.00
Dabigatran
better
1.50
Warfarin
better
Gastrointestinal
• Dabigatran 150 mg twice daily
(35 vs. 24% on warfarin)
– Dyspepsia (abdominal pain upper, abdominal pain,
abdominal discomfort, epigastric discomfort)
– Gastritis-like symptoms (GERD, esophagitis, erosive
gastritis, gastric hemorrhage, hemorrhagic gastritis,
hemorrhagic erosive gastritis, gastrointestinal ulcer)
– GI bleeding more common
RE–LY: GI-Related Discontinuation
D
110 mg
D
150 mg
Warfarin
Naïve
D/C 2° to…
D110 vs.
warfarin
(naïve +
experienced)
Exp
D150 vs.
warfarin (naïve
and
experienced)
P
—————%—————
GI symptoms
2.3
2.1
0.9
0.4
< 0.001
< 0.001
GI bleeding
1.0
1.3
1.0
0.8
NS
NS
Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2009;361:1139-1151.
RE–LY: Myocardial Infarction
Cumulative hazard rates
0.02
Dabigatran150
Dabigatran110
Warfarin
0.01
0.0
0
0.5
1.0
1.5
2.0
2.5
2,983
3,055
2,926
1,410
1,441
1,339
Years of follow-up
Number at risk
D110
6,015
D150
6,076
W
5,896
5,885
5,941
5,896
5,748
5,799
5,757
4,842
4,706
4,635
Dabigatran: Risk of MI and ACS
Across Seven Studies
Dabigatran (n)
ACEv*
No
event
RE–NOVATE (2007)
13
RE–MODEL (2007)
PETRO (2007)
Control (n)
ACEv
No
event
Odds ratio (95% CI)
2,296
9
1,133
0.71 (0.30 – 1.67)
10
1,372
4
690
1.26 (0.39 – 4.02)
2
443
0
70
0.79 (0.04 – 16.73)
175
11,916
63
5,959
1.39 (1.04 – 1.86)
RE–COVER (2009)
4
1,269
2
1,264
1.99 (0.36 – 10.90)
RE–DEEM (2011)
32
1,458
4
313
1.72 (0.60 – 4.89)
RE–NOVATE II (2011)
1
1,009
1
1,002
0.99 (0.06 – 15.90)
Study ( y)
RE–LY original (2009)
1.33 (1.03 – 1.71)
FE model
*Acute coronary event
0.04 0.20 1.00 5.00
Odds ratio (log scale)
Uchino K, Hernandez AV. Arch Intern Med. 2012;172:397-402.
Study Design
Risk factors
Atrial fibrillation
Rivaroxaban
20 mg /d
Randomize
Double-blind /
double-dummy
(N ≈ 14,000)
(15 mg for CrCl 30 – 49 mL/min)
• CHF
• Hypertension
At least 2 or
3 required*
• Age  75 y
• Diabetes
OR
• Stroke, TIA or
systemic embolus
Warfarin
INR target: 2.5
(2.0 – 3.0 inclusive)
Monthly monitoring
Adherence to standard-of-care guidelines
Primary endpoint: Stroke or non-CNS systemic embolism
* Enrollment of patients without prior stroke, TIA or systemic embolism and only 2
factors capped at 10%
ROCKET AF Study Investigators. Am Heart J. 2010;159:340-347.e1.
ROCKET AF: Rivaroxaban
Mean CHADS2 score = 3.5
Rivaroxaban better
Warfarin better
Riva
W
P
—%/y—
Efficacy outcomes
Stroke / systemic embolism
1.7
2.2
< 0.001*
Stroke
1.65
1.96
0.92
Ischemic stroke
1.34
1.42
0.581
Hemorrhagic stroke
0.26
0.44
0.024
Myocardial infarction
0.9
1.1
0.12
All-cause mortality
1.9
2.2
0.07
ICH
0.5
0.7
0.02
Major bleeding
3.6
3.4
0.58
Major GI bleeding
3.15
2.16
< 0.001
Safety outcomes
Major and CRNM bleeding
0
14.9
0.5
1.0
Hazard ratio
Patel MR, et al. N Engl J Med. 2011;365:883-891.
1.5
14.5
2.0
*Noninferiority
0.44
TTR Results (Warfarin) by Region:
ROCKET AF and RE–LY
Percent of subjects
within the study
RE–LY
ROCKET AF
100%
90%
70
80%
60
70%
50
LA
60%
AP
40
50%
EE
30
40%
WE
30%
n = 922
n = 316
n = 1,034
n = 926
n = 2,698
n = 706
10
n = 1,031
n = 1,552
20
NA
n = 1,327
n = 2,167
Average % INR in range
80
0
20%
10%
0%
NA
WE
EE
AP
LA
ROCKET AF
RE–LY
Califf RM.
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Car
diovascularandRenalDrugsAdvisoryCommittee/UCM272005.pdf
Atrial Fibrillation With ≥ 1 Additional Risk Factor for Stroke
Inclusion risk factors
 Age ≥ 75 y
 Prior stroke, TIA, or SE
 HF or LVEF ≤ 40%
 Diabetes mellitus
 Hypertension
Randomize
double blind,
double dummy
(N = 18,201)
Major exclusion criteria
 Mechanical prosthetic valve
 Severe renal insufficiency
 Need for aspirin plus
thienopyridine
Apixaban 5 mg PO twice daily
Warfarin
(2.5 mg twice daily in selected pts*)
(target INR, 2 – 3)
Warfarin/warfarin placebo adjusted by INR/sham INR
based on encrypted point-of-care testing device
Primary outcome: stroke or systemic embolism
Hierarchical testing: non-inferiority for primary outcome,
superiority for primary outcome, major bleeding, death
*2.5 mg was used in patients meeting two or more of the following criteria: age ≥ 80
years, body weight ≤ 60 kg, serum creatinine level ≥ 1.5 mg /dL.
Lopes RD, et al. Am Heart J. 2010;159:331-339.
ARISTOTLE: Apixaban
Mean CHADS2 score = 2.1
Apixaban better
Warfarin better
D150
W
P
—%/y—
Efficacy outcomes
Stroke / systemic embolism
1.27
1.60
0.01
Stroke
1.19
1.51
0.01
Ischemic stroke
0.97
1.05
0.42
Hemorrhagic stroke
0.24
0.47
< 0.001
Myocardial infarction
0.53
0.61
0.37
All-cause mortality
3.52
3.94
0.047
ICH
0.33
0.80
< 0.001
Major bleeding
2.13
3.09
< 0.001
Major GI bleeding
0.76
0.86
0.37
Any bleeding
18.1
25.8
< 0.001
Safety outcomes
0
0.5
1.0
Hazard ratio
Granger CB, et al. N Engl J Med. 2011;365:981-992.
1.5
2.0
New Antithrombotic Therapies
Compared to Warfarin:
Stroke or Systemic Embolism
Dabigatran 150 mg BID
Dabigatran 110 mg BID
Rivaroxaban 20 mg* QD
Apixaban 5 mg† BID
0.5
1
2
*15 mg was used in patients with CrCl 30 – 49 mL/min
† 2.5 mg was used in patients meeting two or more of the following criteria:
age ≥ 80 years, body weight ≤ 60 kg, serum creatinine level ≥ 1.5 mg /dL.
Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2009;361:1139-1151; Patel MR, et al. N Engl
J Med. 2011;365:883-891; Granger CB, et al. N Engl J Med. 2011;365:981-992.
New Antithrombotic Therapies
Compared to Warfarin: Hemorrhagic Stroke
Dabigatran 150 mg BID
Dabigatran 110 mg BID
Rivaroxaban 20 mg* QD
Apixaban 5 mg† BID
0.5
1
2
*15 mg was used in patients with CrCl 30 – 49 mL/min
† 2.5 mg was used in patients meeting two or more of the following criteria:
age ≥ 80 years, body weight ≤ 60 kg, serum creatinine level ≥ 1.5 mg /dL.
Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2009;361:1139-1151; Patel MR, et al. N Engl
J Med. 2011;365:883-891; Granger CB, et al. N Engl J Med. 2011;365:981-992.
New Antithrombotic Therapies
Compared to Warfarin: Major Bleeding
Dabigatran 150 mg BID
Dabigatran 110 mg BID
Rivaroxaban 20 mg* QD
Apixaban 5 mg† BID
0.5
1
2
*15 mg was used in patients with CrCl 30 – 49 mL/min
† 2.5 mg was used in patients meeting two or more of the following criteria:
age ≥ 80 years, body weight ≤ 60 kg, serum creatinine level ≥ 1.5 mg /dL.
Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2009;361:1139-1151; Patel MR, et al. N Engl
J Med. 2011;365:883-891; Granger CB, et al. N Engl J Med. 2011;365:981-992.
Effects Relative to Warfarin of Dabigatran,
Rivaroxaban, and Apixaban
RE–LY
ROCKET AF
ARISTOTLE
Dabigatran
110 mg
twice daily
Dabigatran
150 mg
twice daily
Rivaroxaban
20 mg
once daily
Apixaban
5 mg
twice daily
Reduction in all stroke and systemic
embolism (superior or noninferior)
X
X
X
X
Reduction in major bleeding
X
Reduction in intracranial bleeding
X
X
X
Reduction in ischemic stroke
X
Reduction in fatal bleeding
X
Increase in MI
±
Reduction in all-cause mortality
X
X
X
X
Reduction in cardiovascular mortality
Reduction in gastrointestinal bleeding
X
Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2009;361:1139-1151; Patel MR, et al. N Engl
J Med. 2011;365:883-891; Granger CB, et al. N Engl J Med. 2011;365:981-992.
The ACCP 9 Guidelines:
Antithrombotic therapy for
atrial fibrillation
Gregory Y. H. Lip
Antithrombotic Therapy for Atrial Fibrillation: Antithrombotic
Therapy and Prevention of Thrombosis, 9th ed: American
College of Chest Physicians (ACCP) Evidence-Based Clinical
Practice Guidelines 2012
You JJ, et al. Chest. 2012.141;e531S–e575S.
http://chestjournal.chestpubs.org/content/141/2_suppl/e531S.full.html
2012 ACCP Guidelines for Antithrombotic Therapy in
Patients With AF (I)
Patient features
Recommended antithrombotic therapy
Low risk
(e.g. CHADS2 = 0)
None* (rather than
antithrombotic therapy)
Intermediate risk
(e.g. CHADS2 = 1)
Oral anticoagulation*
(rather than no therapy, ASA, or
ASA + clopidogrel)
High risk
(e.g. CHADS2 ≥ 2)
Oral anticoagulation
(rather than no therapy, ASA, or
ASA + clopidogrel)
Oral anticoagulation
Previous stroke / TIA (rather than no therapy, ASA, or
ASA + clopidogrel)
You JJ, et al. Chest. 2012.141;e531S–e575S.
http://chestjournal.chestpubs.org/content/141/2_suppl/e531S.full.html
* Other factors
that may
influence the
choice are
bleeding risk and
other stroke risk
factors, including
age 65 to 74
years, female
gender and
vascular disease.
The presence of
multiple nonCHADS2 risk factors
may favour OAC
therapy
2012 ACCP Guidelines for Antithrombotic Therapy in
Patients With AF: Recommendations for Dabigatran
 Dabigatran 150 mg twice daily preferable to doseadjusted VKA (target INR, 2.0 – 3.0) for:
 Patients at intermediate or high risk of stroke (e.g. CHADS2 ≥ 1)
 Secondary prevention of cardioembolic stroke
 Grade 2B
Remarks : Dabigatran is excreted primarily by the kidney. It has not been
studied and is contraindicated in patients with severe renal impairment
(estimated creatinine clearance of < 30 mL/min). Clinicians should be aware
that there is no antidote for dabigatran.
 Dabigatran as an alternative to dose-adjusted VKA or
LMWH in patients undergoing elective cardioversion
You JJ, et al. Chest. 2012.141;e531S–e575S.
http://chestjournal.chestpubs.org/content/141/2_suppl/e531S.full.html
2012 ACCP Guidelines for Antithrombotic Therapy in
Patients With AF (II)
Patient features
Recommended antithrombotic therapy
Atrial flutter
Same risk-based recommendations as
for AF
Mitral stenosis
Oral anticoagulation
(rather than no therapy, ASA, or
ASA + clopidogrel)
 Dose-adjusted VKA
(target INR, 2.0 – 3.0)
You JJ, et al. Chest. 2012.141;e531S–e575S.
http://chestjournal.chestpubs.org/content/141/2_suppl/e531S.full.html
2012 ACCP Guidelines for Antithrombotic Therapy
For Patients Undergoing Cardioversion for AF
Patient features
Recommended antithrombotic therapy
AF of > 48 h or
unknown duration with
elective cardioversion
Therapeutic anticoagulation (dose-adjusted VKA,* LMWH, or dabigatran) for
≥ 3 weeks before cardioversion
OR TEE-guided approach with abbreviated anticoagulation
 Therapeutic anticoagulation ≥ 4 weeks after successful cardioversion
AF of known duration
≤ 48 h with elective
cardioversion
Immediate anticoagulation with IV UFH or LMWH, then therapeutic
anticoagulation (dose-adjusted VKA,* LMWH, or dabigatran)
 ≥ 4 weeks after successful cardioversion
Urgent cardioversion
for hemodynamically
unstable AF
Parenteral anticoagulation as soon as possible, then therapeutic
anticoagulation (dose-adjusted VKA,* LMWH, or dabigatran)
 ≥ 4 weeks after successful cardioversion
Cardioversion of
atrial flutter
As for patients undergoing cardioversion for AF

Long-term antithrombotic therapy should follow the risk-based recommendations for AF
*Target INR, 2.0 – 3.0
You JJ, et al. Chest. 2012.141;e531S–e575S.
http://chestjournal.chestpubs.org/content/141/2_suppl/e531S.full.html
ACCP 9 (2012) Recommendations for Patients With
AF and Concomitant ACS or CAD


Condition
Guideline recommendations
AF + stable CAD
(no ACS or revascularization
within the previous year)
 VKA alone (if patient chooses oral anticoagulation) rather than
combination of VKA + ASA (Grade 2C)
CHADS2 ≥ 2
+ BMS or DES
 Triple therapy rather than dual-antiplatelet therapy during the
first month after BMS or first 3 – 6 months after DES
(Grade 2C)
 After initial period of triple therapy, VKA + single-antiplatelet
therapy rather than VKA alone (Grade 2C)
 At 12 months, antithrombotic therapy is suggested as for
patients with AF + stable CAD
CHADS2 = 0 / 1
+ BMS or DES
 Dual-antiplatelet therapy rather than triple therapy during first
12 months after stent placement (Grade 2C)
 At 12 months, antithrombotic therapy is suggested as for
patients with AF + stable CAD
For recommendations in favor of oral anticoagulation, guidelines suggest dabigatran 150 mg twice
daily rather than adjusted-dose VKA.
Triple therapy = VKA + ASA + clopidogrel; dual-antiplatelet therapy = ASA + clopidogrel
You JJ, et al. Chest. 2012.141;e531S–e575S.
http://chestjournal.chestpubs.org/content/141/2_suppl/e531S.full.html
ACCP 9 (2012) Recommendations for Patients With
AF and Concomitant ACS or CAD
Condition
CHADS2 ≥ 1 = ACS
(no stent placement)
CHADS2 = 0
(no stent placement)


Guideline recommendations
 VKA + single-antiplatelet therapy rather than dualantiplatelet or triple therapy during first 12 months after
ACS (Grade 2C)
 At 12 months, antithrombotic therapy is suggested as
for patients with AF + stable CAD
 Dual-antiplatelet therapy rather than VKA therapy +
single-antiplatelet therapy or triple therapy during first
12 months after ACS (Grade 2C)
 At 12 months, antithrombotic therapy is suggested as
for patients with AF + stable CAD
For recommendations in favor of oral anticoagulation, guidelines suggest dabigatran 150 mg twice
daily rather than adjusted-dose VKA.
Triple therapy = VKA + ASA + clopidogrel; dual-antiplatelet therapy = ASA + clopidogrel
You JJ, et al. Chest. 2012.141;e531S–e575S.
http://chestjournal.chestpubs.org/content/141/2_suppl/e531S.full.html
2.1.6 New Oral Anticoagulants vs. VKAs
“Our guideline panel
elected to make
recommendations
only for those drugs
that [had] received
regulatory approval
for use in AF (i.e.,
dabigatran)….”
You JJ, et al. Chest. 2012.141;e531S–e575S.
http://chestjournal.chestpubs.org/content/141/2_suppl/e531S.full.html
34
Novel oral anticoagulants –
Pharmacology and reversal
Richard C. Becker
Oral Anticoagulants:
Pharmacology and Reversal
 Pharmacokinetics /
pharmacodynamics
 Effects on coagulation measures
 Reversal of anticoagulant effect
Unfractionated heparins: antithrombin-dependent
inhibition of FXa and IIa in a 1:1 ratio
Parenteral
1930s
VKAs: indirectly affect synthesis of
multiple coagulation factors
Oral
1940s
LMWH: antithrombin-dependent inhibition of FXa >
inhibition of FIIa (2:1 – 4:1)
Parenteral
Parenteral
1990s
Direct FIIa inhibitors
Parenteral
2000s
Indirect FXa inhibitors
Oral
Direct FXa inhibitors
2008
Oral
Direct FXa
inhibitors
Perzborn E. Nature Rev Drug Dis. 2011;10:61-75.
1980s
Anticoagulants Reduce Procoagulant Substrates in
Proximity to Developing Thrombus
Mann KG. Circulation. 2011;124:225-235.
Targets for Anticoagulant Drug Development
Oral direct
Parenteral indirect
TF/VIIa
X
IX
VIIIa
IXa
AT
Fondaparinux
Va
Apixaban
Rivaroxaban
Edoxaban
Xa
II
IIa
Dabigatran
Fibrinogen
Fibrin
Weitz JI, Bates SM. J Thromb Haemost. 2005;3:1843-1853.
AT
LMWH
AT
UFH
Dabigatran Etexilate
 Competitive inhibitor of thrombin
 Prodrug dabigatran etexilate is converted to
active dabigatran
 Orally active
 Peak plasma concentration 2 hours post-dose;
bioavailability 3.5 – 6.5%
 T½: 14 – 17 hours
 Drug–drug interactions few and don’t influence
1° outcome measures
 P-glycoprotein inhibitors (e.g. quinidine [contraindicated],
amiodarone, verapamil, clarithromycin) increase
systemic exposure
 P-glycoprotein inducers (e.g. rifampin) decrease
systemic exposure
 Eliminated predominantly by kidneys (80%)
Stangier J, et al. J Clin Pharmacol. 2005;45:555-563.
Liesenfeld KH, et al. Br J Clin Pharmacol. 2006;62:527-537.
Stangier J, et al. Br J Clin Pharmacol. 2007;64:292-303.
200 –
150 –
100 –
–4
–3
–2
50 –
–1
0–
|
|
|
|
|
|
|
0
4
8
12
16
20
24
Time (h)
van Ryn J, et al. Thromb Haemost. 2010:103:1116-1127.
20 –
16 –
12 –
8–
4–
0–
TT ratio
TT ratio
Dabigatran
ECT ratio
aPTT ratio
INR
INR and aPTT, ECT (ratio)
Dabigatran concentration
(ng/mL)
Dabigatran Plasma Concentration and
Coagulation Measures
Factor Xa Inhibitors: Properties
Rivaroxaban
Apixaban
Edoxaban
Betrixaban
> 80%
> 50%
> 80%
≈ 35%
Onset of
action (h)
2–4
≈3
1–2
1–3
Half-life (h)
5 – 13
9 – 14
8 – 10
≈ 20
Metabolism
1/3d renal;
2/3d liver
(CYP 450)
Multiple
pathways
(25% renal)
Multiple
(majority
renal)
Via bile
(≈ 5% renal)
Likelihood
of drug
interactions
Low – mod
Low
Low – mod
Low
Bioavailability
12
11
10
9
8
7
6
5
4
3
2
1
0
1000
r = 0.967
b = 0.013
P ≤ 0.0001
Anti-Xa apixaban (ng/mL)
Anti-Xa LMWH (IU/mL)
Apixaban: Pharmacokinetics /
Pharmacodynamics
900
800
700
600
500
400
300
r = 0.967
b = 0.812
P ≤ 0.0001
200
100
0
0 100 200 300 400 500 600 700 800 9001000
0 100 200 300 400 500 600 700 800 9001000
Apixaban plasma concentration (ng/mL)
Becker RC, et al. Thromb Thrombolysis. 2011:32:183-187.
Rivaroxaban: Coagulation Measures
Mean (± SD): All labs
40
aPTT (s)
*
30
Lab A Pathrombin® SL
Lab B STA® APPT
Lab C Pathrombin® SL
Lab D Actin
Lab E Actin
20
Lab F Actin FS
Lab G Actin FS
Lab H HemosiL™, APPT SP
10
Lab I Actin FS
* Statistically significant difference
(before vs. after, P < 0.05)
0
Before
2–3 h after rivaroxaban ingestion
Asmis LM, et al. Thromb Res. 2012:129:492-498.
Prothrombin time (%)
Rivaroxaban: Coagulation Measures
120
Mean (± SD): All labs
100
Lab A Innovin®
Lab B Innovin®
Lab C Innovin®
Lab D Innovin®
Lab E Innovin®
80
*
60
Lab F Innovin®
Lab G Innovin®
Lab H Recombiplastin®
40
20
* Statistically significant difference
(before vs. after, P < 0.05)
Lab I Innovin®
0
Before
2–3 h after rivaroxaban ingestion
Asmis LM, et al. Thromb Res. 2012:129:492-498.
Reversing the Effect of Oral Anticoagulants
 Requirements:
 Low “free”-drug plasma concentration
 Coagulation factor substrate
(concentration / activity) given exceeds
drug inhibitory capacity
 Short drug half-life
 Ability to generate thrombin
Coagulation Factor Replacement Products
 Fresh frozen plasma (FFP)
 Prothrombin complex
concentrate (PCC)
 Activated prothrombin complex
concentrate
 rFactor VIIa
Prothrombin Complex Concentrates Available for
Reversal of Warfarin-Associated Coagulopathy
Factor levels
II
VII
IX
X
≤ 150
≤ 35
100
≤100
24 – 38
<5
24 – 38
24 – 38
Beriplex (CSL Behring), IU/mL
20 – 48
10 – 25
20 – 31
22 – 60
Octaplex (Octapharma), IU/mL
14 – 38
9 – 24
25
18 – 30
Cofact (Sanquin), IU/mL
14 – 35
7 – 20
25
14 – 35
Prothromplex T (Baxter), IU/mL
30
25
30
30
PPPSB–HT, IU/mL
20
20
20
20
30
—
30
130
Product (manufacturer)
Available in US: 3-factor (II, IX, X)
Profilnine SD (Grifols); U/100 FIX U
Bebulin VH (Baxter), IU/mL
Available outside US: 4-factor (II, VII, IX, X)
Available outside US: 3-factor (II, IX, X)
Prothromplex HT (Baxter), IU/mL
Management of Bleeding
Complications With Dabigatran
Patient with bleeding on dabigatran therapy
Mild
bleeding
• Delay next dose
or discontinue
treatment as
appropriate
Moderate–severe
bleeding
•
•
•
•
Symptomatic treatment
Mechanical compression
Surgical intervention
Fluid replacement and
hemodynamic support
• Blood product transfusion
• Oral charcoal application*
(if dabigatran etexilate
ingestion < 2 hours before)
• Hemodialysis
van Ryn J, et al. Thromb Haem. 2010:103:1116-1127.
Life-threatening
bleeding
• Consideration of
rVIIa or PCC*
• Charcoal filtration
* Recommendation based
only on limited non-clinical
data; there is no experience
in volunteers or patients.
Reversal of Contemporary Anticoagulants
Rivaroxaban
20 mg
twice daily
(n = 6)
Rivaroxaban
20 mg
twice daily
(n = 6)
PCC or
placebo
PCC or
placebo
Dabigatran
150 mg
twice daily
(n = 6)
Dabigatran
150 mg
twice daily
(n = 6)
2.5 days
Washout period
(11 days)
Eerenberg ES, et al. Circulation. 2011;124:1573-1579.
2.5 days
Reversal of Dabigatran With PCC
> 120
100
Seconds
100
80
60
50
40
20
aPTT
Thrombin time
0
Dabigatran
150 mg twice daily
for 2.5 days
Seconds
150
0
Dabigatran
150 mg twice daily
for 2.5 days
PCC or
placebo
infusion
PCC or
placebo
infusion
Time
Ecarin clotting time
Placebo
100
PCC
50
0
Time
Dabigatran
150 mg twice daily
for 2.5 days
PCC or
placebo
infusion
Eerenberg E, et al. Circulation. 2011;124:1573-1579.
Reversal of Rivaroxaban With
Prothrombin Complex Concentrate
Placebo
Prothrombin complex concentrate
Endogenous thrombin
potential
Prothrombin time
200
Percentages
Seconds
18
16
14
12
150
100
50
0
10
Time
Time
Rivaroxaban PCC or
20 mg placebo infusion
twice daily
for 2.5 days
Rivaroxaban PCC or
20 mg placebo infusion
twice daily
for 2.5 days
Eerenberg E, et al. Circulation. 2011;124:1573-1579.
Changes in PT/INR With Factor
Replacement in VKA-Treated Patients
PT (sec)
FII (%)
INR
FVII (%)
Antithrombin (%)
Baseline
32.4 ± 4.6
3.0 ± 0.5
31.0 ± 10.5
32.8 ± 16.4
96.0 ± 14.7
+ 3-factor
PCC 0.3 U/mL
21.4 ± 1.3*
1.8 ± 0.2*
67.0 ± 12.4*
36.3 ± 17.5
100.2 ± 17.0
+4-factor
PCC 0.3 U/mL
19.2 ± 2.1*
1.6 ± 0.2*
61.5 ± 11.5*
45.0 ± 23.6
94.3 ± 13.0
+FFP 20%
20.6 ± 1.3*
1.7 ± 0.1*
48.2 ± 9.4
49.5 ± 15.8
98.3 ± 12.7
*P < 0.05 vs. baseline values
Ogawa S, et al. Thromb Haemost. 2011;106:1215-1223.
PCC and FFP Effects on
Thrombin Generation
350
Peak thrombin (nM)
300
250
Warfarin plasma
200
+FFP 20%
+3-f PCC 0.3 U/mL
150
+4-f PCC 0.3 U/mL
100
50
0
0
10
20
Lag time (minutes)
Ogawa S, et al. Thromb Haemost. 2011;106:1215-1223.
30
40
Reversing the Effect of Oral Anticoagulants:
Potential Hazards




Hypervolemia (FFP)
Acute lung injury (FFP)
Heparin (in some PCC)
Thrombosis (PCC, APCC)
 Arterial
 Venous
Complications With
Prothrombin Complex Concentrates
Rate (95% CI)
(0.8 – 2.1)
TE events
1.4%
Death for all causes
10.6% (5.9 – 16.6)
TE events in pts treated for bleeding
1.9%
(1.0 – 3.1)
TE events in pts treated before urgent surgery or
invasive procedures
0.8%
(0.1 – 2.0)
TE events in patients treated with 4-factor PCCs
1.8%
(1.0 – 3.0)
TE events in patients treated with 3-factor PCCs
0.7%
(0.0 – 2.4)
TE events in high-quality studies
2.3%
(0.5 – 5.4)
Viral transmission after PCC administration
1.9%
(0.3 – 4.9)
N = 27 studies in meta-analysis
Dentali F, et al. Thromb Haemost. 2011;106:429-438.
Oral Anticoagulants:
Pharmacology and Reversal
 Pharmacokinetics /
pharmacodynamics
 Effects on coagulation measures
 Reversal of anticoagulant effect
Stroke prevention in AF patients
with chronic kidney disease:
Warfarin or…?
John W. Eikelboom
Questions
1.
What is “chronic kidney disease” and why is it
important for stroke prevention in AF?
2.
What is the efficacy and the safety of warfarin and
of new OACs for stroke prevention of AF patients
with CKD?
3.
What do the guidelines recommend?
Definition and Importance of CKD

Kidney damage or decreased function for
≥ 3 months

Affects 10% of adults

Associated with increased risk of stroke
and bleeding

30% of AF patients have moderate or severe CKD
or ESRD

Severe CKD or ESRD excluded from trials
Herzog CA, et al. Kidney Int. 2011;80:572-586.
Grand’Maison A, et al. Am J Cardiovasc Drugs. 2005; 5:291-305.
Levey A, Coresh J. Lancet. 2012;379:165-180.
Classification of Renal Dysfunction
GFR stage
Description
GFR (mL/min)*
1
Normal or elevated
≥ 90
2
Mild
60 – 89
3
Moderate
30 – 59
4
Severe
15 – 29
5
ESRD
< 15 (or dialysis)
*Or estimated creatinine clearance
Levey A, Coresh J. Lancet. 2012;379:165-180.
Importance of CKD: the Numbers

Moderate or severe (Stage 3/4)

15% prevalence of AF
 1.4-fold ↑in stroke risk vs. general population

End-stage renal disease (Stage 5)

20% prevalence of AF

5 – 10-fold ↑ stroke risk vs. general population
4 – 5% of AF patients have stage 5 disease

Herzog CA, et al. Kidney Int. 2011;80:572-586.
Grand’Maison A, et al. Am J Cardiovasc Drugs. 2005; 5:291-305.
Prevalence of AF in ESRD
Randomly sampled dialysis patients (N = 17,513)
International Dialysis Outcomes and Practice Patterns Study
US general population in 1996 – 1997
Prevalence (%)
30
27
25
22
20
20
18
15
< 55 y
13
12
9
10
5
6
4
55 -– 64 y
65 –74 y
≥ 75 y
7
5
3
0
North America
(US/Canada)
Japan
Europe/ANZ
Wizemann V, et al. Kidney Int. 2010;77:1098-1106.
Stroke and Bleeding in AF Patients With
Moderate CKD (Stage 3)
Percent/y
Percent/y
12 –
11 – Stroke or SE
10 –
9–
8–
7–
6–
5–
4–
3–
2–
1–
0–
Aspirin-treated patients with stage 3 CKD
AVERROES trial
|
|
|
|
|
|
|
35.1 45.3 55.2 64.8 74.9 84.6 96.5
30 – 39
50 – 59
70 – 79
≥ 90
40 – 49
60 – 69
80 – 89
eGFR (mL/min)
10 –
9 – Major bleeding
8–
7–
6–
5–
4–
3–
2–
1–
0–
|
|
|
|
39.0
53.2
67.4
86.4
30 – 34
45 – 59
60 – 74
≥ 75
eGFR (mL/min)
Hart RG, et al. Presented at AHA Scientific Sessions, 2011.
Stroke and Bleeding in AF Patients With
Moderate CKD (Stage 3)
Aspirin-treated patients with Stage 3 CKD vs. eGFR ≥ 60 mL/min
AVERROES Trial
Outcome
Stroke / SE
Major
bleeding
All-cause
mortality
eGFR ≥ 60
Stage 3 CKD
mL/min
——%/y——
HR (95%CI)
2.8
5.6
2.0 (1.4 – 2.9)
0.8
2.2
2.6 (1.4 – 4.9)
3.3
7.1
2.2 (1.6 – 3.0)
Hart RG, et al. Presented at AHA Scientific Sessions, 2011.
Mechanism of Increased Risk of Stroke and
Bleeding in Patients With CKD

CKD associated with hypertension and
cardiac disease

Uremia interferes with normal hemostasis

CKD associated with comorbidities that
predict bleeding

Accumulation of renally cleared anticoagulants…
but not of warfarin (is this an advantage of warfarin
in CKD?)
Herzog CA, et al. Kidney Int. 2011;80:572-586.
Levey A, Coresh J. Lancet. 2012;379:165-180.
Questions
1.
What is “chronic kidney disease” and why is it
important for stroke prevention in AF?
2.
What is the efficacy and the safety of warfarin and
of new OACs for stroke prevention of AF patients
with CKD?
3.
What do the guidelines recommend?
Anticoagulants for AF Patients With CKD
Controversies

Dose of warfarin

Quality of INR control

Efficacy and safety of anticoagulation vs. no
anticoagulation

Efficacy and safety of new oral anticoagulants
compared with warfarin
…in moderate (stage 3) CKD (trial data available)
and severe/end stage (stage 4/5) kidney disease
(no randomized data)
Patients With Renal Dysfunction Require
Lower Doses of Warfarin
Warfarin dose (mg/d)
7
6
5
4
P = 0.02
3
> 60 mL/min
2
30 – 59 mL/min
1
< 30 mL/min
0
P < 0.001
All
pa
tie
nts
wt
CY
P2
C9
/
wt
CY
P2
wt
VK
C9
/
OR
C1
vC
YP
vV
K
2C
9
OR
C
vC
YP
/w
1
tVK
2C
9
OR
C
/v
1
VK
O
RC
1
Limdi NA, et al. J Am Soc Nephrol. 2009;20:912-921.
TTR in AF Patients With ESRD (Stage 5)
Treated With Warfarin

Moderate CKD (Stage 3)


ROCKET AF (CrCl 30 – 49 mL/min): TTR 58%
ESRD (Stage 5)


Limited, low-quality data
TTR < 50%?
Hart RG, et al. Nat Rev Nephrol. In preparation.
OAC for Stroke Prevention in
Moderate CKD (Stage 3)
HR (95% CI)
RR (95% CI)
Warfarin INR 2 – 3
0.24 (0.10 – 0.38)
Apixaban 5 / 2.5 mg twice daily
0.32 (0.18 – 0.55)
0.25
0.50
0.75
Anticoagulant better
1.00
1.25
Aspirin better
Hart RG, et al. Clin J Am Soc Nephrol. 2011;6:2599-2604.
Hart RG, et al. Presented at AHA Scientific Sessions, 2011.
New OACs vs. Warfarin in Patients With
Moderate CKD (Stage 3)
Stroke or systemic embolism
HR (95% CI)
RR (95% CI)
Dabigatran 110 mg twice daily
0.77 (0.51 – 1.18)
Dabigatran 150 mg twice daily
0.55 (0.40 – 0.81)
Rivaroxaban 15 mg once daily
0.86 (0.63 – 1.17)
Apixaban 5 / 2.5 mg twice daily
0.79 (0.57 – 1.20)
0.50
0.75
1.00
New agent better
1.25
1.50
Warfarin better
Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151.
Fox KA, et al. Eur Heart J. 2011;32:2387-2394.
Granger CB, et al. N Engl J Med. 2011;365:981-992.
New Oral Anticoagulants in Patients With
Moderate CKD (Stage 3)
Dabigatran 110 mg
vs. warfarin
Dabigatran 150 mg
vs. warfarin
Rate (%/y)
D110
D150
W
CrCl* 30 – 51
4.39
3.44
5.56
CrCl 50 – 11
1.85
2.17
3.20
CrCl > 80
1.13
1.49
2.06
CrCl 30 – 51
5.36
5.39
5.03
CrCl 50 – 11
3.64
4.09
3.76
CrCl > 80
2.98
5.04
2.90
Pinter
Pinter
0.5
0.88
0.09
0.4
Age < 75 y
Age ≥ 75 y
0.50 1.00 1.50
* Creatinine clearance
in mL/min
Dabigatran
better
Warfarin
better
0.50 1.00 1.50
Dabigatran
better
Warfarin
better
Aspirin, Clopidogrel, and Warfarin in ESRD
41,425 dialysis patients followed for 5 years
1.0
None (n = 24,740)
0.9
Aspirin (n = 9,332)
Survival
0.8
Clopidogrel (n = 1,624)
Warfarin (n = 2,369)
0.7
0.6
0.5
0.4
P < 0.0001
0.3
0
1
2
3
4
5
6
7
Years
Chan KE, et al. J Am Soc Nephrol. 2009;20:872-881.
Warfarin in AF Patients With ESRD
Stroke-free
1,671 AF patients on dialysis followed for average of 1.6 years
1.00
0.98
0.96
0.94
0.92
0.90
0.88
0.86
0.84
0.82
0.80
0.78
0.76
0.74
P < 0.0001
None (n = 480)
Clopidogrel or
aspirin (n = 347)
Warfarin (n = 508)
0
1
2
3
4
5
Years
Chan KE, et al. J Am Soc Nephrol. 2009;20:2223-2233.
Warfarin in ESRD Patients Who Develop AF
Dialysis patients with AF at enrollment (N = 3,245)
International Dialysis Outcomes and Practice Patterns Study
HR for stroke (95% CI)
4.00
2.17
(1.04 – 4.53)
2.00
1.29
(0.45 – 3.68)
1.35
(0.69 – 2.63)
1.00
0.75
0.50
≤ 65 years
66 – 75 years
> 75 years
0.25
Wizemann V, et al. Kidney Int. 2010;77:1098-1106.
Questions
1.
What is “chronic kidney disease” and why is it
important for stroke prevention in AF?
2.
What is the efficacy and the safety of warfarin and
of new OACs for stroke prevention of AF patients
with CKD?
3.
What do the guidelines recommend?
Antithrombotic Guidelines for Stroke
Prevention in Atrial Fibrillation

ACCP 2012


“…we suggest dabigatran 150 mg bid rather than
adjusted-dose VKA therapy…”.
CCS 2012

“…we suggest…that…most patients should receive
dabigatran, rivaroxaban or apixaban in preference to
warfarin...”
You JJ, et al. I. 2012;141:e531S-575S.
Skanes AC, et al. Can J Cardiol. 2012;28:125-136.
Stroke Prevention in AF Patients With CKD
Canadian Cardiovascular Society Atrial Fibrillation Guidelines
2012 Focused Update
Guidance for antithrombotic therapy of patients with
chronic kidney disease is provided in relation
to estimated GFR as follows:
a) eGFR 30 > mL/min: We recommend that such
patients receive antithrombotic therapy
according to their CHADS2 score as detailed in
recommendations for patients
for patients with normal renal function
Strong
recommendation;
high-quality
evidence
Skanes AC, et al. Can J Cardiol. 2012;28:125-136.
Stroke Prevention in AF Patients With CKD
Canadian Cardiovascular Society Atrial Fibrillation Guidelines
2012 Focused Update
b) eGFR 15 – 30 mL/min and not on dialysis: We
suggest that such patients receive
antithrombotic therapy according to their
CHADS2 score as for patients with normal renal
function. The preferred agent for these patients
is warfarin.
c) eGFR < 15 mL/min (on dialysis): We suggest
that such patients not routinely receive either
OAC or ASA for stroke prevention in atrial
fibrillation.
Weak
recommendation;
low-quality
evidence
Weak
recommendation;
OAC: moderatequality evidence;
ASA: low-quality
evidence
Skanes AC, et al. Can J Cardiol. 2012;28:125-136.
Guidelines for Stroke Prevention in AF
Patients With ESRD

Kidney Disease Outcomes Quality Initiative
(KDOQI) 2005


Anticoagulation with careful monitoring due to increased
risk of bleeding
Kidney Disease Improving Global Outcomes
(KDIGO) 2011

Anticoagulation not recommended for primary
prevention; indicated for secondary prevention (history of
stroke)
KDOQI Clinical Practice Guidelines. Am J Kidney Dis. 2005;45:S1-S153.
Herzog CA, et al. Kidney Int. 2011;80:572-586.
Summary

AF patients have high prevalence of CKD

AF patients with CKD are at high risk of stroke
and bleeding

Both warfarin and new OACs are effective in
moderate CKD; new OACs preferred

Anticoagulants have not been rigorously
tested in severe CKD / ESRD; warfarin preferred
(US: dabigatran 75 mg twice daily)

Guidelines do not recommend OACs for primary
stroke prevention in AF patients with ESRD