Utilizzo dei NAO nella FA non valvolare: la forza sociale ... · • Gi à in anticoagulazione /...

Utilizzo dei NAO nella

FA non valvolare:

la forza sociale e

culturale delle

evidenze scientifiche

Paolo Colonna, MD FESCPaolo Colonna, MD FESC

Cardiologia Ospedaliera, Cardiologia Ospedaliera,

Policlinico di BariPoliclinico di BariPresidente eletto nazionale SIECPresidente eletto nazionale SIEC

Guest editor: Paolo Colonna

Sicurezza: emorragie maggioriSicurezza: emorragie maggiori

New oral New oral

anticoagul in AFanticoagul in AF

Position del WG Position del WG

thrombosis ESCthrombosis ESCDe Caterina, De Caterina,

G It Card 2012G It Card 2012

Efficacia: ictus o embolia sistEfficacia: ictus o embolia sist

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 dallRisultati dall’’esperienza nella pratica clinica esperienza nella pratica clinica

-- Food and Drug AdministrationFood and Drug Administration

Cardiovascular, bleeding, and mortality risks in Cardiovascular, bleeding, and mortality risks in

elderly medicare patients treated with elderly medicare patients treated with

dabigatran or warfarin for nondabigatran or warfarin for non--valvular AFvalvular AFGraham et al. Circ 2014 in pressGraham 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

HR: 0.86P=0.006HR: 1.28

P<0.001

HR: 0.80P=0.02

HR: 0.92

P=0.29HR: 0.34P<0.001

HR: 0.97P=0.50

Med

icare

1

RR: 0.88

P=0.05

RR: 1.48P=0.001 RR: 1.27

P=0.12

HR: 0.76P=0.03

RR: 0.41

P<0.001

RR: 0.94P=0.41

RE

-LY

®2

-5




warfarinwarfarin

NOANOA

Warfarin... è arrivato il momento di rottamarlo?

Update sui NAO: Analisi di EfficaciaUpdate sui NAO: Analisi di Efficacia

•• GiGiàà in anticoagulazione / naivein anticoagulazione / naive

•• Solo nel PT INR mal controllato (basso TTR)Solo nel PT INR mal controllato (basso TTR)

•• Parossistica o permanenteParossistica o permanente

•• Nel basso CHADSVasc o HASBLEDNel basso CHADSVasc o HASBLED

•• Nel pregresso ictusNel pregresso ictus

•• Nello scompensoNello scompenso

•• In cardioversione elettricaIn cardioversione elettrica

•• Nelle valvulopatie / protesi biologicheNelle valvulopatie / protesi biologiche

•• In CP ischemica e terapia con ASAIn CP ischemica e terapia con ASA

15

*p-value for interaction.Safety population – on-treatment analysis.

Rivaroxaban Warfarinp-

value*n/N (%) n/N (%)

Overall 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 114/4,401 2.6 140/4,437 3.2

No 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

Newly diagnosed 2/94 2.1 7/100 7.0

ROCKET AF – primary efficacy endpointsubgroup analysis

0.1

Hazard ratio and 95% CIs

1 100.2 0.5 2 5

Favours rivaroxaban Favours warfarin

Patel MR et al, 2011.

Experienced

Naive

Comparison of Trial MetricsComparison of Trial Metrics

RERE--LYLY Rocket AFRocket AF AristotleAristotle EngageAFEngageAF

Time in Time in

Therapeutic Therapeutic

Range Range

(TTR)(TTR)

64%64%67% warfarin67% warfarin--

experiencedexperienced

61% warfarin61% warfarin--

nanaïïveve

Mean 55%Mean 55%

Median Median

58%58%

Mean 62%Mean 62%

Median Median

66%66%

Mean Mean

65%65%

Median Median

68%68%

Efficacy and TTR in 3 SPAF studiesEfficacy and TTR in 3 SPAF studies

FDA Commettee Meeting, 8 sept 2011

April 2012April 2012

Type of AF subanalysis: stroke/systemic embolismFlaker et al. J Am Coll Cardiol ‘12

Type of AF

Paroxysmal

Persistent

Permanent

RE-LY total

1

Hazard ratio

100.1 1

Hazard ratio

100.1

Dabigatran 110Dabigatran 150

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 2011Patel MR et al. N Engl J Med 2011

Sottoanalisi ReLY per punteggio Sottoanalisi ReLY per punteggio

CHADSCHADS22: : ictus ed embolia sistemicaictus ed embolia sistemica

P=0.44

0.5 1.0 1.5Better Dabigatran

Better

Warfarin

0 2.0

Dabigatran 110 BID vs. warfarin

P=0.82

Dabigatran 150 BID

vs. warfarin

0.5 1.0 1.5Better

Dabigatran Better

Warfari

n

0 2.0

Oldgren J et al. Ann Int Med 2011

CHADSCHADS2 2

ScoreScore

Yearly rate (%)Yearly rate (%)

D 110 D 110

mg mg

BIDBIDD 150 D 150

mg BIDmg BID WarfarinWarfarin

00––11 1.061.06 0.650.65 1.081.08

22 1.451.45 0.840.84 1.381.38

33––66 2.122.12 1.881.88 2.732.73

2 / 32 / 3

1 / 21 / 2

1 / 21 / 2

Ictus

HR HR HR

Sanguinam

maggiori

Emorragie

intracranicheAnni

meglio

NAO

meglio

NAO

meglio

NAO

meglio

warfarin

meglio

warfarin

meglio

warfarin

NAO in elderly pts. Colonna Cardiolink 2014NAO in elderly pts. Colonna Cardiolink 2014

6015 110mg BID

6076 150mg BID

6022 W

1462 15mg OD

5619 20mg OD

7081 W

4282.5mg BID

8692 5mg BID

9081 W

7034 30mg OD

7035 60mg OD

7036 W

randomizz 1:1 ciecarandomizz 1:1 cieca

ai due dosaggiai due dosaggi

insuff renale moderata insuff renale moderata

(ClCr 30(ClCr 30--49 ml)49 ml)

2 fra: 2 fra: --etetàà ≥≥ 80, 80,

--peso<60 kg, peso<60 kg,

--Cr Cr ≥≥1.5 mg/dl1.5 mg/dl

randomizz 1:1 cieca +randomizz 1:1 cieca +

ClCr 30ClCr 30--49 ml o49 ml o

peso<60 kg o peso<60 kg o ““farmacifarmaci””

durante lo studiodurante lo studio

Dabigatran compared with warfarin in AF Dabigatran compared with warfarin in AF

and previous TIA or stroke: a subgroup and previous TIA or stroke: a subgroup

analysis of the REanalysis of the RE--LY trialLY trialDiener G, Lancet Neurol 2010Diener G, Lancet Neurol 2010

Time to stroke or SSEin pts with stroke

Efficacy and safety of rivaroxaban in Efficacy and safety of rivaroxaban in

patients with heart failure and AF: patients with heart failure and AF:

insights from ROCKET AFinsights from ROCKET AFVan Diepen et al. Circ H F 2013Van Diepen et al. Circ H F 2013

Analysis of 1.270 pts undergoing Analysis of 1.270 pts undergoing

cardioversion (in ReLY trial) cardioversion (in ReLY trial) Nagarakanti, Circ 2011Nagarakanti, Circ 2011

D110 mg

D150 mg

WarfarinD110 mg

D150 mgWarfarin

0

0,5

1

1,5

2

2,5

3

3,5

4

4,5

5

Str

ok

e / e

mb

olis

m a

t 3

0 d

ay

s

TOE prior cardioversion NO TOE prior

cardioversion

p = n.s.p = n.s.

Rocket-AF 285 pts (JACC ‘13) Aristotle 570 pts (Abs Esc ‘12)

Rationale and design of the XRationale and design of the X--Vert trial Vert trial

in pts scheduled for cardioversionin pts scheduled for cardioversionCappato R Eur Heart J 2014: online onlyCappato R Eur Heart J 2014: online only

XX--VeRT: time to cardioversion by VeRT: time to cardioversion by

cardioversion strategycardioversion strategy

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)

Pati

en

ts (

%)

Delayed cardioversion

p<0.001

1 patient with inadequate

anticoagulation

95 patients with inadequate

anticoagulation

Median time to cardioversion

Da

ys

0

20

40

60

80

100

Early Delayed

p=0.628

p<0.001

Rivaroxaban

VKA

22

days

30

days

Patients cardioverted as scheduled*

Cappato R Eur Heart J 2014: online only










•• In CP ischemicaIn CP ischemica

Esclusione di FA Esclusione di FA ““valvolarevalvolare””

ReRe--LYLY RocketRocket--AFAF AristotleAristotle Engage Engage

AFAF

DabigatranDabigatran RivaroxabanRivaroxaban ApixabanApixaban EdoxabanEdoxaban

Protesi Protesi

meccanicameccanicaEE EE EE EE

Stenosi mitralica Stenosi mitralica

modmod--severaseveraEE EE EE EE

VP severa da VP severa da

operare (sang)operare (sang)EE EE

Protesi biologicaProtesi biologica II

Riparazione Riparazione

valvolare valvolare

((++anello/plast)anello/plast)

II II II II

ReRe--LYLYEzekowitz MD et al. Ezekowitz MD et al.

ACC 2014 AbsACC 2014 Abs

Rocket AFRocket AFBreithardt G et al. Breithardt G et al.

EHJ 2014 onlineEHJ 2014 online

Aristotle Aristotle Avezum A et al. Avezum A et al.

ESC 2013 AbsESC 2013 Abs

Tot trialsTot trials 18.11318.113 14.17114.171 18.20118.201

Tot Tot SVDSVD 3.9503.950 21,8%21,8% 2.0032.003 14,1%14,1% 4.8084.808 26,4%26,4%

MRMR 3.1013.101 78,5%78,5% 1.7561.756 87,7%87,7% 3.5263.526 73,3%73,3%

ARAR 817817 20,7%20,7% 486486 24,3%24,3% 887887 18,4%18,4%

ASAS 471471 11,9%11,9% 215215 10,7%10,7% 384384 8,0%8,0%

TRTR 1.1791.179 29,8%29,8% 2.1242.124 44,2%44,2%

mild MSmild MS 193193 4,9%4,9% 131131 2,7%2,7%

prior valve prior valve

proceduresprocedures106106 5,3%5,3% 251251 5,2%5,2%

SVDSVD: considerata : considerata significativa significativa dal medico che dal medico che

arruolava per i riflessi sulla pratica clinicaarruolava per i riflessi sulla pratica clinica

Clinical characteristics and outcomes Clinical characteristics and outcomes

in AF and native mitral and aortic valve in AF and native mitral and aortic valve

disease in the ROCKET AF trialdisease in the ROCKET AF trialBreithardt G et al. EHJ 2014 onlineBreithardt G et al. EHJ 2014 online

Efficacy: Stroke or systemic embolism

I NAO nei pazienti senza valvulopatia e con I NAO nei pazienti senza valvulopatia e con

valvulopatia lievevalvulopatia lieve--moderatamoderata

•• Valvulopatia moderata + severa (esclusa Valvulopatia moderata + severa (esclusa

SM) senza intervento pianificatoSM) senza intervento pianificato

•• Protesi valvolare biologicaProtesi valvolare biologica

•• Pregressa plastica valvolare Pregressa plastica valvolare ++ anelloanello

•• TAVI o mitral clipTAVI o mitral clip

•• Protesi valvolare meccanicaProtesi valvolare meccanica

•• Stenosi mitralica severaStenosi mitralica severa

•• Valvulopatia con intervento CCH pianificatoValvulopatia con intervento CCH pianificato

2.8

4.84.6

6.3

2.6

4.4 4.3

5.5

2.2

3.9 3.8

5.4

Rateof

MajorBleeding

(% peryear)

Concomitant Use of Antiplatelet Therapy Concomitant Use of Antiplatelet Therapy

with Dabigatran or Warfarinwith Dabigatran or WarfarinDans M et al. Circulation 2013Dans M et al. Circulation 2013

6.952 (38.4%) received concomitant aspirin or clopidogrel, or bo6.952 (38.4%) received concomitant aspirin or clopidogrel, or bothth62% 38% 32+2% 4%

*

Management of antithrombotic therapy in AF pts with ACS and/or undergoing PTCA

Recommendations of ESC, EHRA, EAPCILip G et al. EurHeartJ 2014Lip G et al. EurHeartJ 2014

•• Randomizzazione dosaggiRandomizzazione dosaggi

•• Mono Mono –– bisomministrazione giornalierabisomministrazione giornaliera

•• Comportamento per Comportamento per ↓↓ funzione renalefunzione renale

•• Efficacia sullEfficacia sull’’ictus ischemicoictus ischemico

•• Rischio di sanguinamentoRischio di sanguinamento

•• Dati nella cardioversione elettricaDati nella cardioversione elettrica

•• Controindicati in: protesi valvolari meccaniche Controindicati in: protesi valvolari meccaniche

•• Insuff renale severaInsuff renale severa

•• Neoplasie attive, insuff epatica severaNeoplasie attive, insuff epatica severa

NAO vecchi e nuovi farmaci:

differenze, luci e ombre

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