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la forza sociale e culturale delle evidenze scientifiche
Utilizzo dei NAO nella
FA non valvolare:
la forza sociale e
culturale delle
evidenze scientifiche
Paolo Colonna, MD FESC
Cardiologia Ospedaliera,
Policlinico di Bari
Presidente eletto nazionale SIEC
New oral
anticoagul in AF
Position del WG
thrombosis ESC
De Caterina,
G It Card 2012
Efficacia: ictus o embolia sist
Guest editor: Paolo Colonna
Sicurezza: emorragie maggiori
Efficacy and safety of dabigatran etexilate and warfarin
in ‘real world’ patients with AF: A prospective
nationwide cohort study Larsen T, et al. JACC 2013
Efficacy and safety of dabigatran etexilate and warfarin
in ‘real world’ patients with AF: A prospective
nationwide cohort study Larsen T, et al. JACC 2013
Efficacy and safety of dabigatran etexilate and
warfarin in ‘real world’ patients with atrial fibrillation:
A prospective nationwide cohort study.
Larsen T, et al. JACC 2013
Risultati dall’esperienza nella pratica clinica
- Food and Drug Administration
Cardiovascular, bleeding, and mortality risks in
elderly medicare patients treated with
dabigatran or warfarin for non-valvular AF
Graham et al. Circ 2014 in press
Cardiovascular, bleeding, and mortality risks in
elderly medicare patients treated with
dabigatran or warfarin for non-valvular AF
Graham et al. Circ 2014 in press
Cardiovascular, bleeding, and mortality risks in
elderly medicare patients treated with
dabigatran or warfarin for non-valvular AF
Graham et al. Circ 2014 in press
Cardiovascular, bleeding, and mortality risks in
elderly medicare patients treated with
dabigatran or warfarin for non-valvular AF
Graham et al. Circ 2014 in press
Cardiovascular, bleeding, and mortality risks in
elderly medicare patients treated with
dabigatran or warfarin for non-valvular AF
Graham et al. Circ 2014 in press
•
•
•
•
•
ischemic stroke: 0.80 (0.67-0.96);
intracranial hemorrhage: 0.34 (0.26-0.46);
major gastrointestinal bleeding: 1.28 (1.14-1.44);
acute myocardial infarction: 0.92 (0.78-1.08);
death: 0.86 (0.77-0.96).
In subgroup with dabigatran 75 mgX2, no difference
in risk except ↓ intracranial hemorrhage
Cardiovascular, bleeding, and mortality risks in
elderly medicare patients treated with
dabigatran or warfarin for non-valvular AF
RE-LY®2-5
Medicare1
Graham et al. Circ 2014 in press
HR: 0.97
P=0.50
HR: 0.86
P=0.006
HR: 1.28
P<0.001
HR: 0.80
P=0.02
HR: 0.92
P=0.29
HR: 0.34
P<0.001
RR: 0.88
P=0.05
RR: 0.94
P=0.41
HR: 0.76
P=0.03
RR: 0.41
P<0.001
RR: 1.48
P=0.001
RR: 1.27
P=0.12
Warfarin... è arrivato il momento di rottamarlo?
NOA
warfarin
Update sui NAO: Analisi di Efficacia
•
•
•
•
•
•
•
•
•
Già in anticoagulazione / naive
Solo nel PT INR mal controllato (basso TTR)
Parossistica o permanente
Nel basso CHADSVasc o HASBLED
Nel pregresso ictus
Nello scompenso
In cardioversione elettrica
Nelle valvulopatie / protesi biologiche
In CP ischemica e terapia con ASA
ROCKET AF – primary efficacy endpoint
subgroup analysis
Rivaroxaban
n/N
Overall
Hazard ratio and 95% CIs
Warfarin
(%)
n/N
p(%) value*
189/7,061 2.7 243/7,082 3.4
Previous ASA use
0.94
Yes
70/2,567
2.7
91/2,606
3.5
No
119/4,494 2.7 152/4,476 3.4
Previous VKA use
0.42
Yes Experienced 114/4,401 2.6 140/4,437 3.2
No Naive
75/2,660 2.8 103/2,645 3.9
AF type
0.30
Persistent
159/5,739 2.8 206/5,723 3.6
Paroxysmal
28/1,228
2.3
30/1,259
2.4
2/94
2.1
7/100
7.0
Newly diagnosed
*p-value for interaction.
Safety population – on-treatment analysis.
Patel MR et al, 2011.
0.1
0.2
0.5
Favours rivaroxaban
1
2
5
10
Favours warfarin
15
Update sui NAO: Analisi di Efficacia
•
•
•
•
•
•
•
•
•
Già in anticoagulazione / naive
Solo nel PT INR mal controllato (basso TTR)
Parossistica o permanente
Nel basso CHADSVasc o HASBLED
Nel pregresso ictus
Nello scompenso
In cardioversione elettrica
Nelle valvulopatie / protesi biologiche
In CP ischemica e terapia con ASA
Comparison of Trial Metrics
RE-LY
Time in
Therapeutic
Range
(TTR)
64%
67% warfarinexperienced
61% warfarinnaïve
Rocket AF
Aristotle
Mean 55%
Mean 62%
Median
58%
Median
66%
EngageAF
Mean
65%
Median
68%
Efficacy and TTR in 3 SPAF studies
FDA Commettee Meeting, 8 sept 2011
Update sui NAO: Analisi di Efficacia
•
•
•
•
•
•
•
•
•
Già in anticoagulazione / naive
Solo nel PT INR mal controllato (basso TTR)
Parossistica o permanente
Nel basso CHADSVasc o HASBLED
Nel pregresso ictus
Nello scompenso
In cardioversione elettrica
Nelle valvulopatie / protesi biologiche
In CP ischemica e terapia con ASA
Type of AF subanalysis: stroke/systemic embolism
Flaker et al. J Am Coll Cardiol ‘12
Dabigatran 110
Dabigatran 150
Type of AF
Paroxysmal
Persistent
Permanent
RE-LY total
0.1
1
Hazard ratio
0.1
10
1
10
Hazard ratio
April 2012
Efficacy and Safety of Rivaroxaban Compared to
Warfarin in Patients With Paroxysmal, Persistent,
and Newly Diagnosed AF: The ROCKET-AF Study
Patel MR et al. N Engl J Med 2011
Update sui NAO: Analisi di Efficacia
•
•
•
•
•
•
•
•
•
Già in anticoagulazione / naive
Solo nel PT INR mal controllato (basso TTR)
Parossistica o permanente
Nel basso CHADSVasc o HASBLED
Nel pregresso ictus
Nello scompenso
In cardioversione elettrica
Nelle valvulopatie / protesi biologiche
In CP ischemica e terapia con ASA
Sottoanalisi ReLY per punteggio
CHADS2: ictus ed embolia sistemica
Oldgren J et al. Ann Int Med 2011
Yearly rate (%)
Dabigatran 110 BID
vs. warfarin
D 110
mg
BID
D 150
mg BID
Warfarin
0–1
1.06
0.65
1.08
2
1.45
0.84
1.38
3–6
2.12
1.88
2.73
CHADS2
Score
P=0.44
Dabigatran 150 BID
vs. warfarin
P=0.82
0.5 1.0
0.5 1.0 1.5 2.0 0
0
Better
Better
Better
Warfarin Dabigatran
Dabigatran
1.5 2.0
Better
Warfari
n
2/3
1/2
1/2
NAO in elderly pts. Colonna Cardiolink
2014
Sanguinam
Anni
Ictus
maggiori
HR
meglio
NAO
Emorragie
intracraniche
HR
HR
meglio
warfarin
meglio
NAO
meglio
warfarin
meglio
NAO
meglio
warfarin
6076
6015
6022
150mg BID
110mg BID
W
randomizz 1:1 cieca
ai due dosaggi
5619
20mg OD
insuff renale moderata
(ClCr 30-49 ml)
1462
15mg OD
7081
W
8692
5mg BID
428
2.5mg BID
9081
W
60mg OD
30mg OD
W
7035
7034
7036
2 fra: -età ≥ 80,
-peso<60 kg,
-Cr ≥1.5 mg/dl
randomizz 1:1 cieca +
ClCr 30-49 ml o
peso<60 kg o “farmaci”
durante lo studio
Update sui NAO: Analisi di Efficacia
•
•
•
•
•
•
•
•
•
Già in anticoagulazione / naive
Solo nel PT INR mal controllato (basso TTR)
Parossistica o permanente
Nel basso CHADSVasc o HASBLED
Nel pregresso ictus
Nello scompenso
In cardioversione elettrica
Nelle valvulopatie / protesi biologiche
In CP ischemica e terapia con ASA
Dabigatran compared with warfarin in AF
and previous TIA or stroke: a subgroup
analysis of the RE-LY trial
Diener G, Lancet Neurol 2010
Time to stroke or SSE
in pts with stroke
Update sui NAO: Analisi di Efficacia
•
•
•
•
•
•
•
•
•
Già in anticoagulazione / naive
Solo nel PT INR mal controllato (basso TTR)
Parossistica o permanente
Nel basso CHADSVasc o HASBLED
Nel pregresso ictus
Nello scompenso
In cardioversione elettrica
Nelle valvulopatie / protesi biologiche
In CP ischemica e terapia con ASA
Efficacy and safety of rivaroxaban in
patients with heart failure and AF:
insights from ROCKET AF
Van Diepen et al. Circ H F 2013
Analysis of 1.270 pts undergoing
cardioversion (in ReLY trial)
Nagarakanti, Circ 2011
Stroke / embolism at 30 days
Rocket-AF 285 pts (JACC ‘13)
5
4,5
4
3,5
3
2,5
2
1,5
1
0,5
0
Aristotle 570 pts (Abs Esc ‘12)
p = n.s.
Warfarin
D110 mg
D110 mg
D150 Warfarin
mg
D150 mg
TOE prior cardioversion
NO TOE prior
cardioversion
Rationale and design of the X-Vert trial
in pts scheduled for cardioversion
Cappato R Eur Heart J 2014: online only
X-VeRT: time to cardioversion by
cardioversion strategy
Cappato R Eur Heart J 2014: online only
Median time to cardioversion
Rivaroxaban
VKA
Days
80
p<0.001
60
p=0.628
40
22
days
20
30
days
p<0.001
Patients (%)
100
Patients cardioverted as scheduled*
1 patient with
inadequate
anticoagulation
95 patients with
inadequate
anticoagulation
0
Early
Delayed
Delayed cardioversion
Not performed cardioversion as first scheduled from 21–25 days primarily
due to inadequate anticoagulation (indicated by drug compliance <80% for
rivaroxaban or weekly INRs outside the range of 2.0–3.0 for 3 consecutive
weeks before cardioversion for VKA)
Update sui NAO: Analisi di Efficacia
•
•
•
•
•
•
•
•
•
Già in anticoagulazione / naive
Solo nel PT INR mal controllato (basso TTR)
Parossistica o permanente
Nel basso CHADSVasc o HASBLED
Nel pregresso ictus
Nello scompenso
In cardioversione elettrica
Nelle valvulopatie / protesi biologiche
In CP ischemica
Esclusione di FA “valvolare”
Re-LY
Rocket-AF Aristotle Engage
AF
Dabigatran Rivaroxaban Apixaban Edoxaban
Protesi
meccanica
Stenosi mitralica
mod-severa
VP severa da
operare (sang)
Protesi biologica
E
E
E
E
E
E
E
E
E
E
Riparazione
valvolare
(+anello/plast)
I
I
I
I
I
Tot trials
Re-LY
Rocket AF
Aristotle
Ezekowitz MD et al.
ACC 2014 Abs
Breithardt G et al.
EHJ 2014 online
Avezum A et al.
ESC 2013 Abs
18.113
14.171
18.201
Tot SVD
3.950 21,8%
2.003 14,1%
4.808 26,4%
MR
3.101 78,5%
1.756 87,7%
3.526 73,3%
AR
817 20,7%
486 24,3%
887 18,4%
AS
471 11,9%
215 10,7%
384 8,0%
TR
1.179 29,8%
2.124 44,2%
193 4,9%
131 2,7%
mild MS
prior valve
procedures
106 5,3%
251 5,2%
SVD: considerata significativa dal medico che
arruolava per i riflessi sulla pratica clinica
Clinical characteristics and outcomes
in AF and native mitral and aortic valve
disease in the ROCKET AF trial
Breithardt G et al. EHJ 2014 online
Efficacy: Stroke or systemic embolism
I NAO nei pazienti senza valvulopatia e con
valvulopatia lieve-moderata
•
Valvulopatia moderata + severa (esclusa
SM) senza intervento pianificato
•
•
•
Protesi valvolare biologica
Pregressa plastica valvolare + anello
TAVI o mitral clip
•
•
•
Protesi valvolare meccanica
Stenosi mitralica severa
Valvulopatia con intervento CCH pianificato
Concomitant Use of Antiplatelet Therapy
with Dabigatran or Warfarin
Dans M et al. Circulation 2013
62%
38%
32+2%
4%
6.952 (38.4%) received concomitant aspirin or clopidogrel, or both
6.3
5.5
Rate
of
Major
Bleeding
(% per
year)
4.8
4.6
4.4
5.4
*
4.3
3.9
2.8
2.6
2.2
3.8
Management of antithrombotic therapy in
AF pts with ACS and/or undergoing PTCA
Recommendations of ESC, EHRA, EAPCI
Lip G et al. EurHeartJ 2014
Management of antithrombotic therapy in
AF pts with ACS and/or undergoing PTCA
Recommendations of ESC, EHRA, EAPCI
Lip G et al. EurHeartJ 2014
NAO vecchi e nuovi farmaci:
differenze, luci e ombre
• Randomizzazione dosaggi
• Mono – bisomministrazione giornaliera
• Comportamento per ↓ funzione renale
• Efficacia sull’ictus ischemico
• Rischio di sanguinamento
• Dati nella cardioversione elettrica
• Controindicati in: protesi valvolari meccaniche
• Insuff renale severa
• Neoplasie attive, insuff epatica severa
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