La terapia anticoagulante orale:
quale farmaco scegliere e come
usarlo
Indicazioni e risultati della TAO nella
fibrillazione atriale non valvolare
F. Lombardi
U.O.C. di Malattie Cardiovascolari
Fondazione IRCCS Ospedale Maggiore Policlinico
Dipartimento di Scienze Cliniche e di Comunità
Università degli Studi di Milano
1
2
3
4
CHA2DS2-VASc Thromboembolic Risk Score
www.escardio.org
Bleeding Risk – HAS-BLED Score
www.escardio.org
7
Di Pasquale et al, Int J Cardiol 2013
Comprehensive Meta-Analysis Comparing the
Efficacy and Safety of NOACs with
Warfarin in AF
An Analysis Including 71,683 Patients from
Four Large Randomized Clinical Trials
Christian T. Ruff, MD, MPH
TIMI Study Group
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
9
Pivotal Warfarin-Controlled Trials
Stroke Prevention in AF
Warfarin vs. Placebo
2,900 Patients
NOACs vs. Warfarin
71,683 Patients
ROCKET AF
(Rivaroxaban)
2010
6 Trial of Warfarin vs. Placebo
1989-1993
RE-LY
(Dabigatran)
2009
ENGAGE AF-TIMI 48
(Edoxaban)
2013
ARISTOTLE
(Apixaban)
2011
10
Stroke Prevention in AF
Warfarin vs. Placebo
AFASAK-1 (671)
SPAF (421)
BAATAF (420)
CAFA (378)
SPINAF (571)
EAFT (439)
All Trials (n=6)
64%
100%
50%
Warfarin Better
0%
-50%
-100%
Warfarin Worse
Hart RG, et al. Ann Intern Med 2007;146:857-867.
11
ACTIVE-W: Stroke or SEE
TTR ≥ 65%
TTR < 65%
0.10
RR = 1.83
RR = 1.11
P = 0.47
0.08
P < 0.0001
0.06
0.04
Clopi + ASA
C+A
OAC
VKA
0.02
0.02
0.04
0.06
Clopi + ASA
C+A
OAC
0.0
VKA
0.0
Event Rate (%)
0.08
0.10
P-interaction = 0.013
0.0
0.5
1.0
Years
Connolly SJ, et al. Circulation 2008;118:2029-2037
1.5
0.0
0.5
1.0
1.5
Years
12
ACTIVE-W: Major Bleeding
TTR ≥ 65%
TTR < 65%
RR = 0.68
P = 0.08
0.03
0.03
0.04
P = 0.027
OAC
0.02
0.02
C+A
C+A
0.0
0.01
0.01
OAC
0.0
Event Rate (%)
0.05
RR = 1.55
0.04
0.05
P-interaction = 0.0006
0.0
0.5
1.0
Years
Connolly SJ, et al. Circulation 2008;118:2029-2037
1.5
0.0
0.5
1.0
1.5
Years
13
Comparative PK/PD of NOACs
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
IIa (thrombin)
Xa
Xa
Xa
Hours to Cmax
1-3
2-4
3-4
1-2
Half-life, hours
12-17
5-13
12
10-14
80
33*
27
50
Transporters
P-gp
P-gp
P-gp
P-gp
CYP Metabolism, %
None
32
<32
<4
Target
Renal Clearance, %
CYP = cytochrome P450; P-gp = P-glycoprotein
*33% renally cleared; 33% excreted unchanged in urine
Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2013
Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2011
Weinz et al. Drug Dispos Metab 2009;37:1056–1064
ELIQUIS Summary of Product Characteristics. Bristol Myers Squibb/Pfizer EEIG, UK
Matsushima et al. Am Assoc Pharm Sci 2011; abstract
Ogata, et al. J Clin Pharmacol 2010;50:743–753
Mendell, et al. Am J Cardiovasc Drugs 2013;13:331–342
Bathala, et al. Drug Metab Dispos 2012;40:2250–2255
14
15
NOAC SPAF Trials
Drug
# Randomized
Dose (mg)
Frequency
Dose Adjustment
At Baseline
After Randomization
Target INR (Warfarin)
Design
RE-LY
ROCKET-AF
ARISTOTLE
ENGAGE AF
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
18,113
14,266
18,201
21,105
150, 110
20
5
60, 30
Twice Daily
Once Daily
Twice Daily
Once Daily
No
20 → 15
5 → 2.5
60 → 30
30 → 15
0
21
5
25
No
No
No
>9%
2.0-3.0
2.0-3.0
2.0-3.0
2.0-3.0
PROBE*
2x blind
2x blind
2x blind
*PROBE = prospective, randomized, open-label, blinded end point evaluation
Connolly SJ, 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
Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI:10.1056/NEJMoa1310907
16
Baseline Characteristics
RE-LY
(Dabigatran)
ROCKET-AF
(Rivaroxaban)
ARISTOTLE
(Apixaban)
ENGAGE AF
(Edoxaban)
# Randomized
18,113
14,264
18,201
21,105
Age, years
72 ± 9
73 [65-78]
70 [63-76]
72 [64-78]
Female, %
37
40
35
38
Paroxysmal AF
32
18
15
25
VKA naive
50
38
43
41
Aspirin Use
40
36
31
29
CHADS2
0-1
2
3-6
13
33 32
35
87
30
34
53
47
36
Connolly SJ, 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
Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI:10.1056/NEJMoa1310907
17
Trial Metrics
RE-LY
(Dabigatran)
ROCKET-AF
(Rivaroxaban)
ARISTOTLE
(Apixaban)
ENGAGE AF
(Edoxaban)
Median Follow-Up, years
2.0
1.9
1.8
2.8
Median TTR
66
58
66
68
Lost to Follow-Up, N
20
32
90
1
*TTR, time in therapeutic range
Connolly SJ, 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
Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI:10.1056/NEJMoa1310907
18
All NOACS: Stroke or SEE
Risk Ratio (95% CI)
0.66 (0.53 - 0.82)
RE-LY
[150 mg]
ROCKET AF
0.88 (0.75 - 1.03)
ARISTOTLE
0.80 (0.67 - 0.95)
ENGAGE AF-TIMI 48
0.88 (0.75 - 1.02)
[60 mg]
Combined
0.81 (0.73 - 0.91)
[Random Effects Model]
N=58,541
0.5
Heterogeneity p=0.13
p=<0.0001
Favors NOAC
1
Favors Warfarin
2
Ruff CT, et al. Lancet 2013 [in-press] 19
Secondary Efficacy Outcomes
Risk Ratio (95% CI)
Ischemic Stroke
0.92 (0.83 - 1.02)
p=0.10
Hemorrhagic Stroke
0.49 (0.38 - 0.64)
p<0.0001
MI
0.97 (0.78 - 1.20)
p=0.77
All-Cause Mortality
0.90 (0.85 - 0.95)
p=0.0003
0.2
0.5
Favors NOAC
1
2
Favors Warfarin
Heterogeneity p=NS for all outcomes
Ruff CT, et al. Lancet 2013 [in-press] 20
All NOACS: Major Bleeding
Risk Ratio (95% CI)
0.94 (0.82 - 1.07)
RE-LY
[150 mg]
ROCKET AF
1.03 (0.90 - 1.18)
ARISTOTLE
0.71 (0.61 - 0.81)
ENGAGE AF-TIMI 48
0.80 (0.71 - 0.90)
[60 mg]
Combined
0.86 (0.73 - 1.00)
[Random Effects Model]
p=0.06
N=58,498
0.5
Heterogeneity p=0.001
Favors NOAC
1
Favors Warfarin
2
Ruff CT, et al. Lancet 2013 [in-press]
21
Secondary Safety Outcomes
Risk Ratio (95% CI)
0.48 (0.39 - 0.59)
ICH
p<0.0001
1.25 (1.01 - 1.55)
GI Bleeding
0.2
p=0.043
0.5
Favors NOAC
1
2
Favors Warfarin
Heterogeneity
ICH, p=0.22
GI Bleeding, p=0.009
Ruff CT, et al. Lancet 2013 [in-press]
22
Subgroups: Stroke or SEE
Age
Gender
Diabetes
Prior Stroke or TIA
CrCl
CHADS2 Score
VKA Status
Center-Based TTR
Risk Ratio (95% CI)
P-Interaction
<75
0.85 (0.73 - 0.99)
p=0.38
≥75
0.78 (0.68 - 0.88)
Female
0.78 (0.65 - 0.94)
Male
0.84 (0.75 - 0.94)
No
0.83 (0.74 - 0.93)
Yes
0.80 (0.69 - 0.93)
No
0.78 (0.66 - 0.91)
Yes
0.86 (0.76 - 0.98)
<50
0.79 (0.65 - 0.96)
50-80
0.75 (0.66 - 0.85)
>80
0.98 (0.79 - 1.22)
0-1
0.75 (0.54 - 1.04)
2
0.86 (0.70 - 1.05)
3-6
0.80 (0.72 - 0.89)
Naive
0.75 (0.66 - 0.86)
Experienced
0.85 (0.70 - 1.03)
<66%
0.77 (0.65 - 0.92)
≥66%
0.82 (0.71 - 0.95)
0.5
Ruff CT, et al. Lancet 2013 [in-press]
1
Favors NOAC
p=0.52
p=0.73
p=0.30
p=0.12
p=0.76
p=0.31
p=0.60
2
Favors Warfarin
23
Subgroups: Major Bleeding
Age
Gender
Diabetes
Prior Stroke or TIA
CrCl
CHADS2 Score
VKA Status
Center-Based TTR
Risk Ratio (95% CI)
P-Interaction
<75
0.79 (0.67 - 0.94)
p=0.28
≥75
0.93 (0.74 - 1.17)
Female
0.75 (0.58 - 0.97)
Male
0.90 (0.72 - 1.12)
No
0.71 (0.54 – 0.93)
Yes
0.90 (0.78 - 1.04)
No
0.85 (0.72 - 1.01)
Yes
0.89 (0.77 - 1.02)
<50
0.74 (0.52 - 1.05)
50-80
0.91 (0.76 - 1.08)
>80
0.85 (0.66 - 1.10)
0-1
0.60 (0.45 - 0.80)
2
0.88 (0.65 - 1.20)
3-6
0.86 (0.71 - 1.04)
Naive
0.84 (0.76 - 0.93)
Experienced
0.87 (0.70 - 1.08)
<66%
0.69 (0.59 - 0.81)
≥66%
0.93 (0.76 - 1.13)
0.2
Ruff CT, et al. Lancet 2013 [in-press]
0.5
Favors NOAC
1
2
Favors Warfarin
p=0.29
p=0.12
p=0.70
p=0.57
p=0.09
p=0.78
p=0.022
24
Low Dose Regimens
Efficacy & Safety Outcomes
Dabigatran 110 mg & Edoxaban 30 mg
Risk Ratio (95% CI)
1.03 (0.84 - 1.27)
Stroke or SEE
p=0.74
1.28 (1.02 - 1.60)
Ischemic Stroke
p=0.045
0.33 (0.23 - 0.46)
Hemorrhagic Stroke
p<0.0001
MI
1.25 (1.04 - 1.50)
p=0.019
0.89 (0.83 - 0.96)
All-Cause Mortality
p=0.003
0.65 (0.43 - 1.00)
Major Bleeding
p=0.05
0.31 (0.24 - 0.41)
ICH
p<0.0001
0.89 (0.57 - 1.37)
GI Bleeding
p=0.58
N=26,107
Heterogeneity
P=NS for outcomes except:
Major Bleeding, p=<0.001
GI Bleeding, p=0.01
0.2
0.5
Favors Low Dose NOAC
1
2
Favors Warfarin
Ruff CT, et al. Lancet 2013 [in-press]
25
Dentali et al, Circulation 2012
26
Dentali et al, Circulation 2012
27
From Figure 1 of the Lancet meta-analysis: There were 29
312 patients treated with NOAC drugs and 29 229 patients
treated with warfarin. There were 911 stroke or systemicembolism events in the NOAC group and 1107 in the
warfarin group. The absolute risk of an event was 3.1% on
a NOAC drug and 3.8% on warfarin. The reduction in
absolute risk was 0.7%. In this case, 141 of 142 patients
treated with a NOAC drug received no benefit over
warfarin. Again, our AF patient has a 96.9% chance of not
having an embolic event on a NOAC drug and a 96.2%
chance of not having one on warfarin.
Novel Oral Anticoagulants vs
Warfarin: The Truth is Relative
John Mandrola
DisclosuresDecember 18, 2013
28
From Figure 1: There were 31 830 patients treated with
NOAC drugs and 25 661 treated with warfarin. There
were 186 ICH events in the NOAC group and 317 in the
warfarin group. The absolute risk for ICH was 0.58%
with NOAC drugs and 1.24% with warfarin. The NOAC
drugs prevented 131 ICHs. The absolute difference
between the two groups was a mere 0.65%. Said
another way: for 151 of 152 patients treated, there was
no difference between NOAC drugs and warfarin.
That means we can tell an AF patient similar to the 60
000+ enrolled in the three randomized clinical trials that
he or she has a 99.4% chance of not having an ICH on
a NOAC drug and a 98.8% chance of not having one on
warfarin.
Novel Oral Anticoagulants vs
Warfarin: The Truth is Relative
John Mandrola
DisclosuresDecember 18, 2013
29
Heartwire
Two New Analyses Link Dabigatran to
MI Risk
Michael O'Riordan
July 11, 2013
The risk of MI with dabigatran was also highlighted at the recent
2013 Congress of the International Society on Thrombosis
and Haemostasis meeting in Amsterdam, the Netherlands.
Jonathan Douxfils (University of Namur, Belgium), along with senior
author Dr Jean-Michel Dogné (University of Namur), presented
data from a dose-response meta-analysis of randomized, controlled
trials (RCTs) with outcome data from MI and cardiac events[3].
Ten studies were included in the meta-analysis. Among the 23 839
dabigatran-treated patients, there were 292 MIs. Overall, the risk of
MI was increased 32% compared with the comparator arm, an
increase that was statistically significant. Among patients treated with
the 150-mg dose, the risk of MI was 41% to 45% higher in the
dabigatran arm. The risk of MI only trended toward statistical
significance among those treated with the 110-mg dose (p=0.057).
30
Apostolakis et al, Chest 2013
31
Apostolakis et al, Chest 2013
32
Pivotal Warfarin-Controlled Trials
Stroke Prevention in AF
Warfarin vs. Placebo
2,900 Patients
NOACs vs. Warfarin
71,683 Patients
ROCKET AF
(Rivaroxaban)
2010
6 Trials of Warfarin vs. Placebo
1989-1993
RE-LY
(Dabigatran)
2009
ENGAGE AF-TIMI 48
(Edoxaban)
2013
ARISTOTLE
(Apixaban)
2011
33
Nuove indicazioni?
ACS
Prosthetic valves
Stent thrombosis
54
ATLAS ACS 2 TIMI 51
The trial randomized 15 526 ACS patients to one of the two
doses of rivaroxaban or placebo for a mean of 13 months and
up to 31 months. All patients were taking low-dose (75-100 mg)
aspirin and 93% were also on clopidogrel.
Results of Combined Rivaroxaban Doses vs Placebo
End point
Rivaroxaban combined
doses (%)
CV death/MI/stroke*
8.9
Major non-CABG bleeding 2.1
ICH
0.6
Fatal bleeding
0.3
Placebo (%)
p
10.7
0.6
0.2
0.2
0.008
<0.001
0.009
0.66
Results of Rivaroxaban 2.5 mg Twice Daily Dose vs Placebo
End point
Rivaroxaban 2.5 mg
twice daily (%)
CV death/MI/stroke* 9.1
CV death
2.7
All-cause death
2.9
Major non-CABG
1.8
bleeding
ICH
0.4
Fatal bleeding
0.1
Placebo (%)
HR (95% CI)
p
10.7
4.1
4.5
0.6
0.84 (0.72–0.97 )
0. 66 (0.51–0.86)
0.68 (0.53–0. 87)
3.46 (2.08–5.77)
0.02
0.002
0.002
0.001
0.2
0.2
2.83 (1.02–7.86)
0.67 (0.24–1.89)
0.04
0.45
The US Food and Drug Administration (FDA) has turned away a
proposed expanded indication for rivaroxaban (Xarelto, Bayer/Janssen
Pharmaceuticals) and rejected the new oral anticoagulant as a
treatment for patients with acute coronary syndrome (ACS) [1] .
The FDA issued a complete response letter (CRL) to the manufacturer
today. This is the third time the agency has denied the supplemental
new drug application (sNDA) for the rivaroxaban ACS indication, but
the decision is hardly surprising given last month's FDA advisory
committee meeting.
In addition to denying the sNDA for rivaroxaban in ACS to reduce the
risk of MI, stroke, or death, the FDA also denied an expanded indication
for rivaroxaban in ACS patients to reduce the risk of stent thrombosis.
The company had proposed using rivaroxaban in combination with
standard antiplatelet therapy. (Feb 14,2014).