FIBRILLAZIONE ATRIALE :
NUOVI SCENARI TERAPEUTICI
E CONSEGUENTI IMPLICAZIONI GESTIONALI
HEARTLINE
HSM Genoa Cardiology Meeting
Genova, 22 Ottobre 2011
Giuseppe Di Pasquale
Unità Operativa Cardiologia
Ospedale Maggiore, Bologna
Disclosures
• Member of Advisory Board of
Rivaroxaban, Apixaban, Dronedarone
• Consulting fees / honoraria
- Boehringer Ingelheim
- Bayer AG
- Sanofi Aventis - BMS
Dabigatran,
Antithrombotic Therapy for AFib
Stroke Risk Reduction
Treatment
Better
Warfarin vs.
Placebo/Control
Treatment
Worse
6 Trials
n = 2,900
-64%
Antiplatelet drugs
vs. Placebo
100%
8 Trials
n = 4,876
-19%
50%
0
- 50%
Hart RG et al. Ann Intern Med 2007; 146: 857
Limiti della terapia con antagonisti della Vitamina K
Risposta non
prevedibile
Finestra di
trattamento stretta
(INR range 2-3)
Monitoraggio
routinario dei fattori
della coagulazione
Lente
insorgenza/termine
d’azione
La terapia con
antagonisti
della vitamina
K presenta
diversi limiti
che ne
rendono
difficoltoso
l’impiego
nella pratica
clinica
Frequenti
aggiustamenti della
dose
Numerose interazioni
alimentari
Numerose interazioni
con altri farmaci
Resistenza al
Warfarin
1. Ansell J, et al. Chest 2008;133;160S-198S; 2. Umer Ushman MH, et al. J Interv Card Electrophysiol 2008; 22:129-137;
Nutescu EA, et al. Cardiol Clin 2008; 26:169-187.
Limiti della Terapia Anticoagulante Orale
Conseguenze nella FA
 Un significativo numero di pazienti con FA a rischio di
stroke non riceve la TAO
Steering Committee
Giuseppe Di Pasquale (Chairman ANMCO), Giovanni Mathieu (Chairman
FADOI), Francesco Chiarella, Fabrizio Colombo, Michele Gulizia,
Gualberto Gussoni, Carlo Nozzoli, Domenico Panuccio, Salvatore Pirelli,
Marino Scherillo, Giorgio Vescovo, Massimo Zoni Berisso
Setting of the Study
360 Participating Centers
7148 enrolled patients
164
Cardiology
Departments
Cardiology ward
Cardiology ward and Cath Lab
Cardiology ward with Cath Lab
and CCH
196
Internal Medicine Dept.
Hospital without cardiology
Hospital with cardiology ward
Hospital with cardiology ward
and Cath Lab (with or without
CCH)
From each Center:
Duration of the enrollment 4 weeks
A T A
F
None
Antithrombotic Treatments in
non valvular AF (4.845 pts)
Other ATT
OAC
Limiti della Terapia Anticoagulante Orale
Conseguenze nella FA
 Un significativo numero di pazienti con FA a rischio di
stroke non riceve la TAO
 L’intensità della scoagulazione è spesso al di fuori del
range terapeutico (INR 2.0 – 3.0)
Anticoagulation Control in Real Life in Italy
% of INR Determinations by Range in VKA Treated Patients
Range INR
VKA
Experienced
mean
median
(p25 - p75)
% INR < 2
No
33.4%
28.8%
(15.4% - 47.9%)
% INR < 2
Yes
25.3%
20.0%
(7.7% - 36.4%)
% INR 2.0-3.0
No
47.9%
50.0%
(33.3% - 66.7%)
% INR 2.0-3.0
Yes
56.3%
58.3%
(42.5% - 73.1%)
% INR > 3
No
16.9%
13.3%
(0.0% - 25.0%)
% INR > 3
Yes
17.9%
14.3%
(4.0% - 26.7%)
The Promise of New Anticoagulants
New Anticoagulants
•Coagulation
cascade
•TF/VIIa
•Initiation
•X
•IX
•VIIa
•Propagation
• Drug
•IXa
Indirect: fondaparinux,
idraparinux
•Xa
Direct Oral: rivaroxaban,
apixaban, edoxaban
•Va
•II
•Thrombin activity
•IIa
•Fibrinogen
Tissue factor
pathway inhibitors:
NAPc2
•Fibrin
Direct Parenteral:
bivalirudin
Direct Oral: ximelagatran,
dabigatran, AZD0837
N Engl J Med 2009;361(12):1139-51
N Engl J Med August 10, 2011
N Engl J Med August 28, 2011
Atrial Fibrillation
Phase 3 Study Timelines
Dabigatran
RE-LY
Published 2009
2009
2010
Rivaroxaban
Edoxaban
ROCKET AF
Published
August 2011
ENGAGE AF TIMI 48
Study ongoing
Expected 2012
2011
2012
AVERROES
Published
February 2011
ARISTOTLE
Published
August 2011
Apixaban
Atrial Fibrillation
Phase 3 Study Timelines
Dabigatran
RE-LY
Published 2009
2009
2010
Rivaroxaban
Edoxaban
ROCKET AF
Published
August 2011
ENGAGE AF TIMI 48
Study ongoing
Expected 2012
2011
2012
AVERROES
Published
February 2011
ARISTOTLE
Published
August 2011
Apixaban
The RE-LY Study:
Randomized Evaluation of
Long-term anticoagulant therapY
Dabigatran Compared to Warfarin in 18,113 Patients with
Atrial Fibrillation at Risk of Stroke
Connolly SJ., et al. NEJM published online on Aug 30th 2009.
DOI 10.1056/NEJMoa0905561
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation
RE-LY® – study design
Atrial fibrillation with ≥ 1 risk factor
Absence of contraindications
R
Warfarin
1 mg, 3 mg, 5 mg
(INR 2.0-3.0)
N=6000
Dabigatran etexilate
110 mg bid
N=6000
Dabigatran etexilate
150 mg bid
N=6000
 Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin
 Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up
Ezekowitz MD, et al. Am Heart J 2009;157:805-10.
Connolly SJ., et al. NEJM published online on Aug 30th 2009.
DOI 10.1056/NEJMoa0905561
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation
TIME TO FIRST STROKE OR SSE
Dabigatran 150 mg BID
Dabigatran 110 mg BID
Warfarin
Cumulative hazard rates
0.05
0.04
RRR
35%
RR 0.90
(95% CI: 0.74–1.10)
P<0.001 (NI)
P=0.30 (Sup)
0.03
0.02
RR 0.65
(95% CI: 0.52–0.81)
P<0.001 (NI)
P<0.001 (Sup)
0.01
0.0
0
0.5
1.0
1.5
2.0
2.5
3.0
Years
RR = relative risk; RRR = relative risk reduction; SSE = systemic embolism.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Connolly SJ, et al. N Engl J Med 2010;363:1875-1876.
v2 November 2010
21
MAJOR BLEEDING RATES
RR 0.93 (95% CI: 0.81–1.07)
P=0.32 (superiority)
RR 0.80 (95% CI: 0.70–0.93)
P=0.003 (superiority)
Rate per year (%)
5.0
RRR
20%
4.0
3.0
3.32
2.0
3.57
2.87
1.0
0
Events/n:
D150 mg BID
D110 mg BID
Warfarin
399 / 6,076
342 / 6,015
421 / 6,022
D = dabigatran; RR = relative risk; RRR = relative risk reduction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Connolly SJ, et al. N Engl J Med 2009;361:1139-1151.
v2 November 2010
22
MAJOR BLEEDING AND COMPONENTS
P value
P value
D150
vs. W
D110
vs. W
3.57
0.32
0.003
1.24
1.85
0.03
<0.001
2.06
1.83
1.92
0.39
0.65
1.56
1.15
1.07
0.001
0.52
Dabigatran
Dabigatran
150 mg
110 mg
Number of patients
6,076
6,015
6,022
Major bleeding rate
(% per year)
3.32
2.87
Life threatening
1.49
Non-life threatening
Gastro-intestinal
Characteristic
Warfarin
D = dabigatran; W = warfarin. Data represent %/year.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Connolly SJ, et al. N Engl J Med 2010;363:1875-1876.
v2 November 2010
23
Hemorrhagic stroke
RR 0.31 (95% CI: 0.17–0.56)
p<0.001 (sup)
RR 0.26 (95% CI: 0.14–0.49)
50
p<0.001 (sup)
45
Number of events
40
RRR
74%
RRR
69%
0.38%
30
20
10
14
0.12%
12
0.10%
0
D110 mg BID
D150 mg BID
Warfarin
6,015
6,076
6,022
Connolly SJ., et al. NEJM published online on Aug 30th 2009.
DOI 10.1056/NEJMoa0905561
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation
Mortalità per qualsiasi causa
Mortalità vascolare
RE-LY Subgroup Analyses
RE-LY Subgroup Analysis:
Prior TIA or Stroke
Lancet Neurology 2010; 9: 1157-63
0.08
Prior stroke/TIA: time to primary outcome
# at Risk
D110 1195
D150 1233
W
1195
Year 0.5
1160
1201
1160
1.0
1132
1164
1126
1.5
908
938
895
2.0
573
617
565
2.5
289
321
262
0.06
0.04
Dabigatran 110 mg
0.02
Dabigatran 150 mg
0.0
Cumulative Hazard Rates
Warfarin
0
0.5
1.0
1.5
Years of follow-up
2.0
2.5
Intra-cranial bleeding rates in patients
with prior stroke or TIA
RR 0.20 (95% CI: 0.08–0.47)
p<0.001
RR 0.41 (95% CI: 0.21–0.79)
P=0.007
30
Number of events
30
20
RRR 59%
RRR 80%
13
10
6
0
D110 mg bid
1195
D150 mg bid
Warfarin
1233
1195
RE-LY Subgroup Analysis:
Age & Renal Function
Circulation 2011;123:2363-72
AGE AND RENAL FUNCTION SUBGROUP
ANALYSIS: STROKE AND NON-CNS EMBOLISM
Annual rate (%)
D 110 mg D 150 mg
Warfarin
BID
BID
D 110 mg BID
vs. warfarin
Age (yrs)
<65
1.48
0.69
1.35
65–74
1.26
0.98
1.43
≥75
1.87
1.43
2.1
Creatinine clearance (mL/min)
30–50
2.26
1.33
2.65
51–80
1.65
1.24
1.76
>80
0.92
0.72
1
0.5
0
Dabigatran
better
1.0
D 150 mg BID
vs. warfarin
P=0.76
P=0.072
P=0.58
P=0.036
1.5
2.0
Warfarin
better
0.5
0
Dabigatran
better
1.0
1.5
2.0
Warfarin
better
BID = twice daily; CNS = central nervous system; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.
v2 November 2010
34
AGE AND RENAL FUNCTION SUBGROUP
ANALYSIS: MAJOR BLEEDING
Annual rate (%)
D 110 mg D 150 mg
Warfarin
BID
BID
D 110 mg BID
vs. warfarin
Age (yrs)
<65
0.76
0.79
2.32
65–74
2.12
2.45
3.08
≥75
4.21
4.81
4.09
Creatinine clearance (mL/min)
30–50
5.07
4.85
5.17
51–80
2.62
3.04
3.44
>80
1.36
1.88
2.18
0.5
0
Dabigatran
better
1.0
D 150 mg BID
vs. warfarin
P=0.0003
P=0.0001
P=0.1
P=0.091
1.5
2.0
Warfarin
better
0.5
0
Dabigatran
better
1.0
1.5
2.0
Warfarin
better
BID = twice daily; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.
v2 November 2010
35
AGE AND RENAL FUNCTION SUBGROUP
ANALYSIS: HAEMORRHAGIC STROKE
Annual rate (%)
D 110 mg D 150 mg
Warfarin
BID
BID
D 110 mg BID
vs. warfarin
Age (yrs)
<65
0.05
0.05
0.38
65–74
0.08
0.08
0.31
≥75
0.2
0.15
0.47
Creatinine clearance (mL/min)
30–50
0.26
0.12
0.58
51–80
0.12
0.09
0.47
>80
0.03
0.08
0.13
0.5
0
Dabigatran
better
1.0
D 150 mg BID
vs. warfarin
P=0.51
P=0.75
P=0.67
P=0.4
1.5
2.0
Warfarin
better
0.5
0
Dabigatran
better
1.0
1.5
2.0
Warfarin
better
BID = twice daily; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.
v2 November 2010
36
EMA approves PRADAXA with the flexibility
of two dosing regimens
Overall the 150 mg bid dose is recommended; the 110
mg bid dose is indicated for elderly patients aged 80
years at higher risk of bleeding and for those
taking verapamil
4 August 2011
ANTITHROMBOTIC PROPHYLAXIS IN AF
NEW PERSPECTIVES
 New oral direct thrombin inhibitors
(other than ximelagatran)
 Oral Factor Xa inhibitors
New Oral Direct FXa Inhibitors Under Investigation
for Stroke Prevention in Atrial Fibrillation
Rivaroxaban
Bayer
Phase III
Apixaban
BMS / Pfizer
Phase III
Edoxaban
Daiichi Sankyo
Phase III
Betrixaban
Portola / Merck
Phase II
Darexaban
Astellas Pharma
Phase II
LY 517717
Lilly
Planned
TAK – 442
Takeda
Planned
New Oral Direct FXa Inhibitors Under Investigation
for Stroke Prevention in Atrial Fibrillation
Rivaroxaban
Bayer
Phase III
Apixaban
BMS / Pfizer
Phase III
Edoxaban
Daiichi Sankyo
Phase III
Betrixaban
Portola / Merck
Phase II
Darexaban
Astellas Pharma
Phase II
LY 517717
Lilly
Planned
TAK – 442
Takeda
Planned
N Engl J Med August 10, 2011
ROCKET AF – study design
Randomized, double-blind, double-dummy, event-driven
Non-valvular AF
N=14,264
OR
≥2* of the following:




CHF
Hypertension
Age ≥75 years
Diabetes
R
30-day follow-up
Rivaroxaban 20 mg once daily#
End of study
 History of stroke,
TIA or non-CNS SE
Warfarin target INR 2–3
~14 – 40 months‡
*Enrolment of patients with <3 risk factors or without prior stroke/TIA or non-CNS SE was limited to 10%.
#Patients with CrCl 30–49 ml/min: 15 mg rivaroxaban once daily.
‡Duration of therapy varied for each patient as study was event-driven.
Patel MR et al, 2011
42
ROCKET AF – primary efficacy endpoint
on and off treatment
Rivaroxaban
n/N
(% per year)
Warfarin
n/N
(% per year)
Per protocol,
on treatment
188/6,958
(1.7)
Safety,
on treatment
ITT
Non-inf.
241/7,004
(2.2)
0.79 (0.66,0.96)
<0.001
189/7,061
(1.7)
243 /7,082
(2.2)
0.79 (0.65,0.95)
269/7,081
(2.1)
306/7,090
(2.4)
0.88 (0.75,1.03)
ITT, on
treatment
188
(1.7)
240
(2.2)
0.79 (0.66,0.96)
0.02
ITT, off
treatment
81 (4.7)
66 (4.3)
1.10 (0.79,1.52)
0.58
Primary efficacy endpoint: stroke or systemic embolism
ITT on- and off-treatment: post hoc analyses
Hazard ratio
and 95% CIs
p-value
Hazard ratio
(95% CI)
Sup.
0.02
<0.001
0.12
0.5
Favours
rivaroxaban
Patel MR et al, 2011.
2
1
Favours
warfarin
44
ROCKET AF – bleeding analysis
Rivaroxaban
(N=7,111)
Parameter
Warfarin
(N=7,125)
n (% per year) n (% per year)
Hazard ratio
(95% CI)
Principal safety
endpoint
1,475 (14.9)
1,449 (14.5)
1.03 (0.96,1.11)
Major bleeding
395 (3.6)
386 (3.4)
1.04 (0.90,1.20)
Haemoglobin drop
(≥2 g/dl)
305 (2.8)
254 (2.3)
1.22 (1.03,1.44)*
Transfusion
183 (1.6)
149 (1.3)
1.25 (1.01,1.55)*
Critical organ
bleeding
91 (0.8)
133 (1.2)
0.69 (0.53,0.91)*
55 (0.5)
84 (0.7)
0.67 (0.47,0.93)*
27 (0.2)
55 (0.5)
0.50 (0.31,0.79)*
1,185 (11.8)
1,151 (11.4)
1.04 (0.96,1.13)
Intracranial
haemorrhage
Fatal bleeding
Non-major clinically
relevant bleeding
Major bleeding from gastrointestinal site (upper, lower and rectal):
rivaroxaban=224 events (3.2%); warfarin=154 events (2.2%); p<0.001*
Safety population – on-treatment analysis; *Statistically significant
Hazard ratio
and 95% CIs
0.2
0.5 1
2
5
Favours
Favours
rivaroxaban
warfarin
Patel MR et al, 2011.
45
New Oral Direct FXa Inhibitors Under Investigation
for Stroke Prevention in Atrial Fibrillation
Rivaroxaban
Bayer
Phase III
Apixaban
BMS / Pfizer
Phase III
Edoxaban
Daiichi Sankyo
Phase III
Betrixaban
Portola / Merck
Phase II
Darexaban
Astellas Pharma
Phase II
LY 517717
Lilly
Planned
TAK – 442
Takeda
Planned
N Engl J Med 2011;364(9): 806-17
APIXABAN Phase 3 Clinical Trial vs Aspirin
to Prevent Stroke or Embolism in AF Pts
AVERROES
≈ 1.6 years
Patient characteristics
• Aged 50 years
• 1 additional risk
factor for stroke
• Not suitable for vitamin K
antagonist
N=5600
Randomization
• Atrial fibrillation
Apixaban 2.5 mg bid or 5
mg bid
Aspirin 81-324 mg qd
Primary outcome measures:
• Time to composite outcome of stroke or systemic embolism
• Time to major bleeding
N Engl J Med 2011;364(9): 806-17
AVERROES - Primary Efficacy Outcome
N Engl J Med 2011;364(9): 806-17
AVERROES - Primary Safety Outcome
N Engl J Med 2011;364(9): 806-17
N Engl J Med August 28, 2011
Atrial Fibrillation with at Least One
Additional Risk Factor for Stroke
Inclusion risk factors
Age ≥ 75 years
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 oral twice daily
Warfarin
(2.5 mg BID in selected patients)
(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
N Engl J Med 2011
Primary Outcome
Stroke (ischemic or hemorrhagic) or systemic embolism
P (non-inferiority)<0.001
21% RRR
Apixaban 212 patients, 1.27% per year
Warfarin 265 patients, 1.60% per year
HR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011
No. at Risk
Apixaban
Warfarin
9120
9081
8726
8620
8440
8301
6051
5972
3464
3405
1754
1768
N Engl J Med 2011
Efficacy Outcomes
Outcome
Stroke or systemic embolism*
Apixaban
Warfarin
(N=9120)
(N=9081)
Event Rate Event Rate
(%/yr)
(%/yr)
HR (95% CI)
P
Value
1.27
1.60
0.79 (0.66, 0.95)
0.011
1.19
1.51
0.79 (0.65, 0.95)
0.012
Ischemic or uncertain
0.97
1.05
0.92 (0.74, 1.13)
0.42
Hemorrhagic
0.24
0.47
0.51 (0.35, 0.75) <0.001
0.09
0.10
0.87 (0.44, 1.75)
0.70
All-cause death*
3.52
3.94
0.89 (0.80,0.998)
0.047
Stroke, SE, or all-cause death
4.49
5.04
0.89 (0.81, 0.98)
0.019
Myocardial infarction
0.53
0.61
0.88 (0.66, 1.17)
0.37
Stroke
Systemic embolism (SE)
N Engl J Med 2011
Major Bleeding
ISTH definition
31% RRR
Apixaban 327 patients, 2.13% per year
Warfarin 462 patients, 3.09% per year
HR 0.69 (95% CI, 0.60–0.80); P<0.001
No. at Risk
Apixaban
Warfarin
9088
9052
8103
7910
7564
7335
5365
5196
3048
2956
1515
1491
N Engl J Med 2011
Bleeding Outcomes
Outcome
Primary safety outcome:
ISTH major bleeding*
Apixaban
Warfarin
(N=9088)
(N=9052)
Event Rate Event Rate
(%/yr)
(%/yr)
HR (95% CI)
P Value
2.13
3.09
0.69 (0.60, 0.80)
<0.001
Intracranial
0.33
0.80
0.42 (0.30, 0.58)
<0.001
Gastrointestinal
0.76
0.86
0.89 (0.70, 1.15)
0.37
Major or clinically relevant
non-major bleeding
4.07
6.01
0.68 (0.61, 0.75)
<0.001
GUSTO severe bleeding
0.52
1.13
0.46 (0.35, 0.60)
<0.001
TIMI major bleeding
0.96
1.69
0.57 (0.46, 0.70)
<0.001
Any bleeding
18.1
25.8
0.71 (0.68, 0.75)
<0.001
N Engl J Med 2011
New Oral Direct FXa Inhibitors Under Investigation
for Stroke Prevention in Atrial Fibrillation
Rivaroxaban
Bayer
Phase III
Apixaban
BMS / Pfizer
Phase III
Edoxaban
Daiichi Sankyo
Phase III
Betrixaban
Portola / Merck
Phase II
Darexaban
Astellas Pharma
Phase II
LY 517717
Lilly
Planned
TAK – 442
Takeda
Planned
ENGAGE-AF-TIMI 48
(Study for Evaluation of DU-176b vs Warfarin in Subjects with AF)
n~16,500
AF on ECG < 12 mos
Intended oral A/C
CHADS2 Score > 2
R
Low Exposure Strategy
DU-176b 30 mg QD
(n=5500)
Randomization Strata:
1. CHADS2 2-3 vs 4-6
2. Drug clearance
High Exposure Strategy
DU-176b 60 mg QD
(n=5500)
Median Duration of Followup 24 months
1º EP = Stroke or SEE (Noninferiority Boundary HR 1.38)
2º EP = Stroke or SEE or All-Cause Mortality
Safety EP’s = Major Bleeding, Hepatic Function
Active Control
Warfarin
(n=5500)
Atrial Fibrillation
Phase 3 Study Timelines
Dabigatran
RE-LY
Published 2009
2009
2010
Rivaroxaban
Edoxaban
ROCKET AF
Published
August 2011
ENGAGE AF TIMI 48
Study ongoing
Expected 2012
2011
2012
AVERROES
Published
February 2011
ARISTOTLE
Published
August 2011
Apixaban
E’ possibile un confronto tra
dabigatran, rivaroxaban e apixaban ?
Somiglianze e differenze tra gli studi
PK/PD of 5 Novel Oral Agents
Target
Hrs to Cmax
CYP Metabolism
Half-Life
Renal Elimination
Dabigatran
Apixaban
Rivaroxaban
Edoxaban
(DU-176b)
Betrixaban
(PRT054021)
IIa
(thrombin)
Xa
Xa
Xa
Xa
2
1-3
2-4
1-2
NR
None
15%
32%
NR
None
12-14h
8-15h
9-13h
8-10h
19-20h
80%
40%
33%
35%
<5%
CYP = cytochrome P450; NR = not reported
Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14
Ericksson BI et al. Clin Pharmacokinet 2009; 48: 1-22
Ruff CR et al. Am Heart J 2010; 160:635-41
Phase III AF Trials
Re-LY
ROCKETAF
ARISTO
TLE
ENGAGE
AF-TIMI 48
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
150, 110
BID
20 (15*)
QD
5 (2.5*)
BID
60*, 30*
QD
N
18,113
14,266
18,206
>21,000
Design
PROBE
2x blind
2x blind
2x blind
AF criteria
AF x 1
< 6 mths
AF x 2
(>1 in <30d)
AF or AFl x 2
<12 mths
AF x 1
< 12 mths
50%
38%
43%
40% goal
Drug
Dose (mg)
Freq
% VKA naive
*Dose adjusted in patients with ↓drug clearance. **Max of 10% with CHADS-2 score = 2 and no stroke/TIA/SEE
PROBE = prospective, randomized, open-label, blinded end point evaluation
VKA = Vitamin K antagonist
RELY
CHADS2 Mean
0-1 (%)
2
(%)
3+ (%)
ROCKET AF
CHADS2 Mean
2 (%)
3 (%)
4 (%)
5 (%)
6 (%)
ARISTOTLE
CHADS2 Mean
0-1 (%)
2 (%)
3+ (%)
C. Michael Gibson, M.S., M.D.
Dabigatran 110
mg
Dabigatran 150
mg
Warfarin
2.1
32.6
34.7
32.7
2.2
32.2
35.2
32.6
2.1
30.9
37.0
32.1
Rivaroxaban
Warfarin
3.5
13
43
29
13
2
3.5
13
44
28
12
2
Rivaroxaban
Warfarin
2.1
34
35.8
30.2
2.1
34
35.8
30.2
3+
87%
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011
Comparison of Trial Metrics
RE-LY
Time in
Therapeutic
Range (TTR)
C. Michael Gibson, M.S., M.D.
64%
67% warfarinexperienced
61% warfarin-naïve
ROCKET AF
Mean 55%
Median 58%
ARISTOTLE
Mean 62%
Median 66%
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011
Stroke
Warfarin
No. of events
NOAC
HR 95% CI
(%/yr)
171 (1.44)
186 (1.58)
0.91
0.74-1.12
122 (1.01)
186 (1.58)
0.64
0.51-0.81
184 (1.65)
221 (1.96)
0.85
0.70-1.03
Apixaban 199 (1.19)
250 (1.51)
0.79
0.65-0.95
Dabi 110
(ITT)
Dabi 150
(ITT)
Riva
(safety AT)
(ITT)
0.0
ITT: Intention to Treat – AT: as treated
0.5
1.0
Favors NOAC
Not head to head comparison – For illustrative purposes only – adapted from references 1-4
1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6.
3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92.
1.5
Favors warfarin
2.0
Ischemic or Unspecified Stroke
NOAC
Warfarin
No. of events
(%/yr)
HR
95% CI
0.881.39
0.590.97
0.751.17
0.741.13
159 (1.34)
143 (1.21)
1.11
111 (0.92)
143 (1.21)
0.76
149 (1.34)
161 (1.42)
0.94
Apixaban* 162 (0.97)
*
175 (1.05)
0.92
Dabi 110
(ITT)
Dabi 150
(ITT)
Riva*
(safety AT)
(ITT)
0.0
0.5
Favors NOAC
1.0
1.5
2.0
Favors warfarin
*Only ischemic strokes are counted here. The no. of strokes with unknown type were 7 and 11 in the rivaroxaban and warfarin groups,
respectively.
** Unknown type of stroke occurred in 14 patients in the apixaban group and 21 patients in the warfarin group. Among the patients with
ischemic
strokes,tohemorrhagic
transformation
occurred in 12 patients with apixaban and 20 patients with warfarin.
ITT: Intention
Treat – AT: as
treated.
Not head to head comparison – For illustrative purpose only – adapted from references 1-4
1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6.
3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92.
Hemorrhagic Stroke
NOAC
Warfarin
HR
No. of events
(%/yr)
95%
CI
45 (0.38)
0.31 0.17-0.56
12 (0.10)
45 (0.38)
0.26 0.14-0.49
29 (0.26)
50 (0.44)
0.59 0.37-0.93
Apixaban 40 (0.24)
78 (0.47)
0.51 0.35-0.75
Dabi 110 14 (0.12)
(ITT)
Dabi 150
(ITT)
Riva
(safety AT)
(ITT)
0.0
0.5
Favors NOAC
ITT: Intention to Treat – AT: as treated.
Not head to head comparison – For illustrative purpose only – adapted from references 1-4
1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6.
3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92.
1.0
1.5
Favors warfarin
2.0
Major Bleeding
NOAC
Warfarin
HR 95% CI
No. of events
(%/yr)
Dabi 110
342 (2.87)
421 (3.57)
0.80
0.700.93
Dabi 150
399 (3.32)
421 (3.57)
0.93
0.811.07
Riva
395 (3.6)
386 (3.4)
1.04
0.901.20
Apixaban
327 (2.13)
462 (3.09)
0.69
0.600.80
0.0
0.5
1.0
Favors NOAC
Not head to head comparison – For illustrative purpose only – adapted from references 1-4
1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6.
3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92.
1.5
Favors warfarin
2.0
Death From Any Cause
NOAC
Warfarin
HR 95% CI
No. of events
(%/yr)
446 (3.75)
487 (4.13)
0.91
0.801.03
438 (3.64)
487 (4.13)
0.88
Rivaroxab 582 (4.5)
an (ITT)
Rivaroxab 208 (1.87)
an (safety
AT)
Apixaban 603 (3.52)
632 (4.9)
0.92
250 (2.21)
0.85
0.771.00
0.821.03
0.701.02
669 (3.94)
0.89 0.80-0.99
Dabi 110
(ITT)
Dabi 150
(ITT)
(ITT)
0.0
0.5
Favors NOAC
1.0
1.5
Favors warfarin
Not head to head comparison – For illustrative purpose only – adapted from references 1-4
1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6.
3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92.
2.0
Lo studio RE-LY: è iniziato il crepuscolo dei dicumarolici?
G Ital Cardiol 2010; 11 (4): 263-268
William Turner, The Fighting Temeraire (National Gallery, Londra)
G Ital Cardiol 2011; 12(9): 556-65
Nuovi Anticoagulanti Orali non VKA Antagonisti
Vantaggi
•
•
•
•
•
•
•
Dose – risposta prevedibile : dose fissa giornaliera
Non necessità di monitoraggio dell’anticoagulazione
Elevata efficacia e sicurezza
Significativa riduzione del rischio emorragico
Inizio e termine d’azione rapidi: non necessità di bridge con eparina
Minime interazioni farmacologiche
Assenza di interazioni alimentari
Di Pasquale G, Riva L, G Ital Cardiol 2011; 12: 556-65
Nuovi Anticoagulanti Oralianti non VKA Antagonisti
Svantaggi
• Aggiustamento empirico del dosaggio
• Necessità di nuovi test laboratoristici da eseguire in caso di eventi
emorragici o trombotici
• Difficoltà di valutare l’aderenza del paziente alla terapia
• Mancanza di antidoto in caso di sovradosaggio o emorragie
• Inizio e termine d’azione rapidi: potenziale svantaggio nei pazienti
con bassa aderenza terapeutica
• Possibile ridotta consapevolezza della terapia da parte del paziente
• Costo elevato
Di Pasquale G, Riva L, G Ital Cardiol 2011; 12: 556-65
Nuove Strategie Antitrombotiche per la Profilassi
Tromboembolica della Fibrillazione Atriale
Problemi Aperti
• Per quali pazienti (A chi ?)
Nuove Strategie Antitrombotiche per la Profilassi
Tromboembolica della Fibrillazione Atriale
Problemi Aperti
• Per quali pazienti (A chi ?)
• Con quale sorveglianza (Come ?)
Nuove Strategie Antitrombotiche per la Profilassi
Tromboembolica della Fibrillazione Atriale
Problemi Aperti
• Per quali pazienti (A chi ?)
• Con quale sorveglianza (Come ?)
• Con quale responsabilità di presa in carico (Da chi ?)
Nuove Strategie Antitrombotiche per la Profilassi
Tromboembolica della Fibrillazione Atriale
Problemi Aperti
• Per quali pazienti (A chi ?)
Nuove Strategie Antitrombotiche per la Profilassi
Tromboembolica della Fibrillazione Atriale
Futuri Scenari Clinici
• Pazienti con FA di nuovo riscontro con indicazioni
all’anticoagulazione (naive)
Nuove Strategie Antitrombotiche per la Profilassi
Tromboembolica della Fibrillazione Atriale
Futuri Scenari Clinici
• Pazienti con FA di nuovo riscontro con indicazioni
all’anticoagulazione (naive)
• Pazienti con FA già in TAO in presenza di specifiche
problematiche
Nuove Strategie Antitrombotiche per la Profilassi
Tromboembolica della Fibrillazione Atriale
Futuri Scenari Clinici
• Pazienti con FA di nuovo riscontro con indicazioni
all’anticoagulazione (naive)
• Pazienti con FA già in TAO in presenza di specifiche
problematiche
• Pazienti con FA già in TAO in assenza di specifiche
problematiche
Nuove Strategie Antitrombotiche per la Profilassi
Tromboembolica della Fibrillazione Atriale
Futuri Scenari Clinici
• Pazienti con FA di nuovo riscontro con indicazioni
all’anticoagulazione (naive)
• Pazienti con FA già in TAO in presenza di specifiche
problematiche
• Pazienti con FA già in TAO in assenza di specifiche
problematiche
• Pazienti con FA attualmente non in TAO
Nuove Strategie Antitrombotiche per la Profilassi
Tromboembolica della Fibrillazione Atriale
Futuri Scenari Clinici
• Pazienti con FA di nuovo riscontro con indicazioni
all’anticoagulazione (naive)
NAO come terapia di scelta, soprattutto nei pazienti con
difficoltà logistiche per la gestione della TAO
Nuove Strategie Antitrombotiche per la Profilassi
Tromboembolica della Fibrillazione Atriale
Futuri Scenari Clinici
•
Pazienti con FA già in TAO in presenza di specifiche problematiche
▪ qualità TAO non soddisfacente (TTR < 55-50%)
▪
▪
▪
▪
▪
dosi giornaliere molto basse di VKA
difficoltà logistiche (assistenza domiciliare)
pregressa emorragia cerebrale
farmaci associati interferenti necessari
non disponibilità ai controlli periodici
proponibile lo switch dalla TAO ai NAO
Nuove Strategie Antitrombotiche per la Profilassi
Tromboembolica della Fibrillazione Atriale
Futuri Scenari Clinici
• Pazienti con FA già in TAO in assenza di specifiche
problematiche
non ragionevole uno switch immediato ai NAO
da non trascurare però le preferenze del paziente
adeguatamente informato
Nuove Strategie Antitrombotiche per la Profilassi
Tromboembolica della Fibrillazione Atriale
Futuri Scenari Clinici
• Pazienti con FA non in TAO
▪
pazienti esclusi dalla TAO a causa di elevato rischio emorragico
dubbi candidati per i NAO
(dabigatran bassa dose in pazienti selezionati ?)
▪ pazienti esclusi dalla TAO per problemi logistici
possibili candidati ai NAO, previo accertamento
della compliance
Nuove Strategie Antitrombotiche per la Profilassi
Tromboembolica della Fibrillazione Atriale
Problemi Aperti
• Per quali pazienti (A chi ?)
• Con quale sorveglianza (Come ?)
Dalla Sorveglianza Laboratoristica
alla Sorveglianza Clinica
• Colloquio ad inizio terapia (medico, infermiere)
• Controlli clinici periodici (ogni 3-4 mesi ?) per verificare
tolleranza, compliance, eventi emorragici (visite brevi)
• Controlli periodici funzionalità renale (cadenza
individualizzata)
• Trasferimento di risorse infermieristiche e mediche
dall’Ambulatorio TAO alla Sorveglianza clinica
Nuove Strategie Antitrombotiche per la Profilassi
Tromboembolica della Fibrillazione Atriale
Problemi Aperti
• Per quali pazienti (A chi ?)
• Con quale sorveglianza (Come ?)
• Con quale responsabilità di presa in carico (Da chi ?)
Presa in carico del paziente con FA anticoagulato
con i nuovi anticoagulanti orali
Possibili Attori
• Centri TAO FCSA (solo 20% dei pazienti anticoagulati)
• Cardiologie Ospedaliere
(Servizio Ambulatoriale ± Ambulatorio TAO)
• Cardiologie Territoriali
• Medicine Interne / Geriatrie
(Servizio Ambulatoriale ± Ambulatorio TAO)
• Medico di Medicina Generale (NCP, MMG associati)
Attività essenziali
per il trattamento con VKA o NAO
AVK
NAO
Visita prescrizione
SI
SI
Giusta indicazione e dose
SI
SI
Informazione /educazione pz.
SI
SI
Controlli laboratorio
SI
NO
Aggiustamento dose
SI
NO
Controllo compliance
NO
SI
Guida per condizioni rischio
SI
SI
Controllo clinico periodico
NO
SI
Rivaroxaban
TF/VIIa
 Selective, direct Factor Xa inhibitor1
 High oral bioavailability2
X
IX
 Rapid onset of action3
 Half-life:2–4
 5–9 hours in young healthy
individuals
 11–13 hours in the elderly
VIIIa
IXa
Rivaroxaban
Va
Xa
 Dual mode of elimination:5
II
 1/3 of active drug excreted unchanged
by the kidneys
 2/3 of drug metabolized by the liver;
IIa
half of which is excreted renally,
half excreted via the
Fibrinogen
hepatobiliary route
1. Perzborn E et al, 2005; 2. Kubitza D et al, 2005;
3. Kubitza D et al, 2005; 4. Kubitza D et al, 2008;
5. Weinz C et al, 2009.
Fibrin
Adapted from Weitz JI et al, 2005; 2008.
95
Rivaroxaban Once-daily oral direct factor Xa inhibition
Compared with vitamin K antagonism for prevention
of stroke and Embolism Trial in Atrial Fibrillation
ROCKET AF – study design
Randomized, double-blind, double-dummy, event-driven
Non-valvular AF
N=14,264
OR
≥2* of the following:




CHF
Hypertension
Age ≥75 years
Diabetes
R
30-day follow-up
Rivaroxaban 20 mg once daily#
End of study
 History of stroke,
TIA or non-CNS SE
Warfarin target INR 2–3
~14 – 40 months‡
*Enrolment of patients with <3 risk factors or without prior stroke/TIA or non-CNS SE was limited to 10%.
#Patients with CrCl 30–49 ml/min: 15 mg rivaroxaban once daily.
‡Duration of therapy varied for each patient as study was event-driven.
Patel MR et al, 2011
97
ROCKET AF – primary efficacy endpoint
Stroke or systemic embolism
Cumulative event rate (%)
6
HR=0.79 (0.66, 0.96)
5
Warfarin
p<0.001 (non-inferiority)
4
3
Rivaroxaban
2
1
0
0
Number of subjects at risk
Rivaroxaban
6,958
Warfarin
7,004
120
240
480
600
360
Days since randomization
720
840
6,211
6,327
5,786
5,911
2,472
2,539
1,496
1,538
5,468
5,542
4,406
4,461
3,407
3,478
Per-protocol population – as treated
Patel MR et al, 2011.
98
ROCKET AF – major bleeding by site
Rivaroxaban
(N=7,111)
Warfarin
(N=7,125)
395 (5.6)
386 (5.4)
Gastrointestinal (upper, lower, rectal)#
224 (3.2)
154 (2.2)
Intracranial‡
55 (0.8)
84 (1.2)
37 (0.5)
56 (0.8)
Non-traumatic‡
33 (0.5)
54 (1.8)
Traumatic
4 (0.1)
2 (0.03)
Intraventricular
2 (0.03)
4 (0.1)
Subdural haematoma
12 (0.2)
22 (0.3)
Subarachnoid
4 (0.1)
1 (0.01)
Epidural haematoma
0
1 (0.01)
Macroscopic haematuria
26 (0.4)
21 (0.3)
Bleeding associated with non-cardiac surgery
19 (0.3)
26 (0.4)
Intraocular/retinal
17 (0.2)
24 (0.3)
Intraarticular
16 (0.2)
21 (0.3)
Epistaxis
13 (0.2)
14 (0.2)
Site*
Major bleeding, n (%)
Intraparenchymal‡
*Site based on blinded adjudication.
#Combined gastrointestinal bleed rate p<0.001; ‡p<0.05
Patel MR et al, 2011.
99
ROCKET AF – all-cause mortality
Hazard ratio
and 95% CIs
Rivaroxaban
(N=7,061)
Warfarin
(N=7,082)
n
(% per year)
n
(% per year)
Hazard ratio
(95% CI)
208 (1.9)
250 (2.2)
0.85 (0.70,1.02)
Vascular death
170 (1.5)
193 (1.7)
0.89 (0.73, 1.10)
Non-vascular death
21 (0.2)
34 (0.3)
0.63 (0.36, 1.08)
Unknown cause
17 (0.2)
23 (0.2)
0.75 (0.40, 1.41)
Endpoints
All-cause mortality
Safety population – on-treatment analysis
Patel MR et al, 2011.
0.2
0.5 1
Favours
rivaroxaban
2
5
Favours
warfarin
100
ROCKET AF – secondary endpoints
Rivaroxaban
(N=7,061)
Warfarin
(N=7,082)
n (% per year)
n (% per year)
Hazard ratio
(95% CI)
Composite of stroke, nonCNS SE,
vascular death
346 (3.1)
410 (3.6)
0.86 (0.74, 0.99)*
Composite of stroke, non-CNS
SE, vascular death and MI
433 (3.9)
519 (4.6)
0.85 (0.74, 0.96)*
All-cause stroke
184 (1.7)
221 (2.0)
0.85 (0.70, 1.03)
Non-CNS SE
5 (0.04)
22 (0.2)
0.23 (0.09, 0.61)*
MI
101 (0.9)
126 (1.1)
0.81 (0.63, 1.06)
Vascular death
170 (1.5)
193 (1.7)
0.89 (0.73, 1.10)
208 (1.9)
250 (2.2)
0.85 (0.70, 1.02)
Endpoints
Components of major secondary
endpoints
All-cause mortality
Safety population – on-treatment analysis. *Statistically significant
Patel MR et al, 2011.
102
ROCKET AF – primary efficacy endpoint
subgroup analysis
Rivaroxaban
Overall
Sex
Male
Female
Age (years)
<75
≥75
Weight (kg)
≤70
70–≤90
>90
CrCl (ml/min)
<50
50–80
>80
n/N
189/7,061
(%)
2.7
n/N
243/7,082
(%)
3.4
p-value*
0.92
103/4,270
86/2,791
2.4
3.1
136/4,283
107/2,799
3.2
3.8
0.11
107/3,988
82/3,073
2.7
2.7
119/4,005
124/3,077
3.0
4.0
0.78
63/2,004
92/3,022
34/2,033
3.1
3.0
1.7
78/2,008
129/3,133
36/1,940
3.9
4.1
1.9
0.72
50/1,485
91/3,290
47/2,278
3.4
2.8
2.1
60/1,456
128/3,396
54/2,221
*p-value for interaction
Safety population – on-treatment analysis
Patel MR et al, 2011.
Hazard ratio and 95% CIs
Warfarin
4.1
3.8
2.4
0.1
0.2
0.5
Favours
rivaroxaban
1
2
5
Favours
warfarin
10
103
ROCKET AF – primary efficacy endpoint
centre-based INR control*
Rivaroxaban
(% per year)
Warfarin
(% per year)
Hazard ratio
(95% CI)
0.0–50.6%
1.8
2.5
0.70 (0.48, 1.03)
50.7–58.5%
1.9
2.2
0.89 (0.62, 1.29)
58.6–65.7%
1.9
2.1
0.89 (0.62, 1.28)
65.7–100.0%
1.3
1.8
0.74 (0.49, 1.12)
Better INR control
cTTR
cTTR, centre-based time in therapeutic range
Based on Rosendaal method with all INR values included
*p-value for interaction=0.74
Safety population (N=7,061 [rivaroxaban], N=7,082 [warfarin])
Patel MR et al, 2011.
Hazard ratio and 95% CIs
2
1
0.5
Favours rivaroxaban Favours warfarin
104
ROCKET AF – conclusions
 Based on the prespecified primary efficacy outcome:
 A once-daily fixed dose regimen of rivaroxaban was non-inferior to warfarin
for prevention of stroke or non-CNS systemic embolism
 Rivaroxaban was superior to warfarin while patients were taking study drug
 Less MIs and vascular death with rivaroxaban (not statistically significant)
 Safety:





Similar overall incidence of bleeding and adverse events
Increase in gastrointestinal bleeds with rivaroxaban
fewer intracranial haemorrhages with rivaroxaban
less fatal bleeding with rivaroxaban
Less overall mortality (not statistically significant)
 Implication:
 Rivaroxaban, once approved in the indication, is a once-daily, proven
alternative to warfarin with superior efficacy ‘on treatment’, similar overall
bleeding and fewer intracranial haemorrhages
105
Additional safety outcomes:
Liver enzyme elevations
D110
D150
Warfarin
N=6,015
N=6,076
N=6,022
ALT or AST
>3xULN
121
111
126
%
2.0
1.8
2.1
ALT or AST
>3xULN and
bilirubin >2xULN
11
14
22
%
0.2
0.2
0.4
No. of patients
Connolly SJ., et al. NEJM published online on Aug 30th 2009.
DOI 10.1056/NEJMoa0905561
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation
RE-LY in perspective
Meta-analysis of ischaemic stroke
or systemic embolism
Category
W vs placebo
W vs W low dose
W vs ASA
W vs ASA + clopidogrel
W vs ximelagatran
W vs dabigatran 150
0
0.3
0.6
0.9
Favours warfarin
Camm J.: Oral presentation at ESC on Aug 30th 2009.
1.2
1.5 1.8 2.0
Favours other treatment
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation
Lo studio RE-LY: è iniziato il crepuscolo dei dicumarolici?
G Ital Cardiol 2010; 11 (4): 263-268
William Turner, The Fighting Temeraire (National Gallery, Londra)
Eerenberg ES et al. Circulation. 2011; 124:1573-79