Anticoagulazione in neurologia:algoritmi decisionali nel post-ictus

Giuseppe MicieliDipartimento di Neurologia d’Urgenza

IRCCS Fondazione Istituto Neurologico Nazionale C Mondino

Pavia

L’ Ictus ischemico nel Registro SUN Lombardia

Aterosclerosi dei grossi vasi

23%

Cardioembolismopossibile/probabile

31%

Occlusione dei piccoli vasi

25%

Da cause diverse10%

Da cause non determinate

11%

Cardioembolic cerebral infarction

• The most severe ischaemicstroke subtype, with in-hospital mortality rate (6-27%)

• Substantial number of patientswith neurological dysfunctionat the time of hospital discharge

• Risk of early embolic recurrencebetween 1 and 10%

Arboix A, Aliò J. Rev Cardiovasc Ther 2011;9:367-369

Post-stroke atrial fibrillation

Admission to the emergency room

In-hospital stay

Sposato L et al. Lancet Neurol 2015;14:377-387

FA atriale: cardiogena o neurogena?

Chung MK et al, Circulation 2001

Gonzalez Toledo ME et al, J Stroke and Cerebrovasc Dis 2013

Corrales-Medina VF et al, Lancet 2013

Proteina C reattiva

Risposta non prevedibile

Monitoraggio routinario dei fattori della

coagulazione

Lenta insorgenza/termine

d’azione Resistenza a Warfarin

La terapia con antagonisti della

vitamina K presenta diversi

limiti che ne rendono

difficoltoso l’impiego nella pratica clinica

Numerose interazioni con altri farmaci

Numerose interazioni alimentari

Frequenti aggiustamenti della dose

Finestra terapeutica ristretta

(INR range 2-3)

Amin A. Oechsner J 2016;16:531-541

DOACs: an innovatoryapproachto anticoagulation

DOACs comparison

Ruff C et al. Lancet 2014:383:955-962

Major bleeding

Stroke or systemic embolism

Raccomandazione 12.5.4 FORTE A FAVORE Prevenzione Secondaria

In caso di ictus ischemico o TIA attribuibile a FAnv in paziente che non assumeva terapia antitrombotica è raccomandato l’impiego di anticoagulanti orali (anticoagulanti orali diretti o AVK).

Raccomandazione 12.5.6 FORTE A FAVORE Prevenzione Secondaria

In caso di ictus ischemico o TIA attribuibile a FAnv è raccomandato l’utilizzo dei NAO per la loro almeno uguale efficacia e per la loro maggiore sicurezza in confronto alla terapia con AVK. *GPP la decisione è indipendente dal risultato di CHA2DS2-VASc e di HAS-BLED e interessa tutti i pazienti compresi quelli già in trattamento con antiaggreganti piastrinici e AVK.

•Si deve utilizzare (raccomandazione “positiva forte”) •Si potrebbe utilizzare (raccomandazione “positiva debole”) •Non si dovrebbe utilizzare (raccomandazione “negativa debole”) •Non si deve utilizzare (raccomandazione “negativa forte”)

Metodo GRADE

Cumulative rates for stroke/

systemicembolism (a)

and major bleeding (b)

The SAMURAI-NVAF study

(1137 pts;2001-2014)

Arihiro S et al. Int J Stroke 2016;11:565-574

Cumulative rates for the secondaryoutcomes

The SAMURAI-NVAF study

Arihiro S et al. Int J Stroke 2016;11:565-574

Ischemic events Ischemic stroke or TIA

Intracranial hemorrhage Mortality

HR for eachpairwise

propensity-matched DOAC

medicationcomparison (a)

Yao X et al. J Am Heart Assoc 2016;5:e003725 doi:10.1161/AHA. 116.003725

15.390 pts

28.614 pts

32.350 pts

Medicare AdvantageOctober 1 – June 30, 2015

HR for eachpairwise

propensity-matched DOAC

medicationcomparison (a)

Yao X et al. J Am Heart Assoc 2016;5:e003725 doi:10.1161/AHA. 116.003725

15.390 pts

28.614 pts

32.350 pts

Medicare AdvantageOctober 1 – June 30, 2015

0,80,7

1,9

2,1

0,4

0,9

0,0

0,5

1,0

1,5

2,0

2,5

Stroke/SE Allstrokes

Death Majorbleeding

ICH GIbleeding

XANTUS

Xarelto

1,7 1,71,9

3,6

0,5

2,0

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

4,0ROCKET AF

Xarelto

#Includes prior stroke, SE or TIA; *Events per 100 patient-years

1. Patel MR et al, N Engl J Med 2011;365:883–891; 2. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466;3. Connolly SJ et al, N Engl J Med 2009;361:1139-51; 4. Connolly SJ et al, N Engl J Med 2011;364:806-17

CHADS2 Prior stroke#

ROCKET AF1 3.5 55%

XANTUS2 2.0 19%

XANTUS vs ROCKET AFComparison of Main Outcomes

CHADS2

Prior

stroke#

RE-LY3 2.1 19%

ARISTOTLE4 2.0 19%

Risk of bleeding in Rivaroxaban comparedwith VKAs in NVAF patients

Sanmartin-Fernandez M, Marzal-Martin D. Clin Appl Thromb Haemost 2016:1-14

Independent FDA Medicare results compared to RE-LY®* patients

*Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg together without stratification by dose. Numbers above bars denote HRs vs warfarin. 1. Graham DJ et al. Circulation 2015; 131:157-64; 2. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 3. Connolly SJ et al. N Engl J Med 2010;363:1875–6; 4. Pradaxa®: EU SPC, 2014; 5. Connolly SJ et al. N Engl J Med 2014; 371:1464–5

0

1

2

3

4

5

Incid

en

ce

ra

te p

er

10

0p

ers

on

-ye

ars Warfarin

Dabigatran 150 mg & 75 mg BIDcombined

HR: 0.86P=0.006HR: 1.28

P<0.001

HR: 0.80P=0.02

HR: 0.92P=0.29HR: 0.34

P<0.001

HR: 0.97P=0.50

Me

dic

are

1

0

1

2

3

4

5

Ischaemic stroke ICH Major bleeding GI bleeding MI Mortality

Event

rate

(% p

er

year)

Warfarin

Dabigatran 150 mg BID

RR: 0.88P=0.05

RR: 1.48P=0.001 RR: 1.27

P=0.12

HR: 0.76P=0.03

RR: 0.41P<0.001

RR: 0.94P=0.41

RE

-LY

®2-

5

Cumulative incidence of nonpersistenceaccording to OAC treatment

Lamberts M et al. J Am Heart Assoc 20176:e004517. DOI: 10.1161/JAHA.116.004517)

Permanent discontinuation of NVKs in reallife NVAF patients

Vedovati MC et al. Int J Cardiol 2017.dx.doi.org/10.1016/j.ijcard.2017.01.098

1305 patients

473 Dabigatran425 Rivaroxaban407 Apixaban

Utilizzo VKAs e DOACs in Italia

Temporal trends in OAC initiation and overallutilization in Denmark (2005-2015)

GaldsbollK et al. Eur Heart J 2017;38:899.906

Oral anticoagulation prescription rates amongAF patients with CHA2Ds2VASc score > 2

Shah RU et al. Neuroepidemiol2016;47:201-209

University UtahHealth SciencesCenter

6,688 AF pts(Jan 1, 2008-June 30, 2015)

Relative rate of OAC use among AF patients with CHA2Ds2VASc score > 2

Shah RU et al. Neuroepidemiol 2016;47:201-209

OAC prescription rates according to CHA2Ds2VASc score

Shah RU et al. Neuroepidemiol 2016;47:201-209

Distribution of CHA2DS2-VASc and HAS-BLED scores among

OAC naivepatients

UK primary care5 242 patients with NVAF newly

prescribed apixaban, rivaroxaban, dabigatran or

vitamin K antagonists (VKAs) between 1 December 2012 and 31

October 2014

Johnson ME et al. BMI Open 2016;6:e: 011471.doi:10.1136/bmjopen-2016-011471

Practical guidance to the use of DOACsin NVAF patients

Canavero I et al. Clin Appl Thromb Hemost 2017 (in press)

80% of patients with recurrent stroke had the event within 2-3 days

Distribuzione dei pazienti con strokeed AF trattati e non

trattati con AC

Canavero I et al. 2016 (dati non pubblicati)

Fattori favorenti la prescrizione della terapia anticoagulante durante il ricovero

Registro SUN Lombardia 2015

Casistiche di pazienti con stroke

ed FA trattati con

DOAC in fase acuta

Days prior to initiating oral anticoagulants The SAMURAI-NVAF study

Toyoda K et al. Int J Stroke 2015;10:836-842

Timing of anticoagulation therapy flow chart on patients with acute ischemic stroke and AF

Canavero I et al. Clin Appl Thromb Hemost 2017 (in press)

Common risk factors for dementia and atrial fibrillation

Shah AD et al. J Atrial Fibrillation 2016;8(5):53-60

Factors to be considered in DOACsprescription in patients with dementia

Canavero I et al. Clin Appl Thromb Hemost 2017 (in press)

Cumulative incidence of major bleedingaccording to OAC treatment

Lamberts M et al. J Am Heart Assoc 20176:e004517. DOI: 10.1161/JAHA.116.004517)

USA nation-wide administrative registries

History of AFOAC : Aug 22, 2011-

Dec 31, 2015

54 321 patients73 years mean age2.9 mean CHA2DS2-VASc

score

7,693 Apixaban6,715 Rivaroxaban15,413 Dabigatran24,230 Warfarin

Major bleeding incidence rates and HRPropensity Score matched cohorts

Lip GYH et al. Thromb Hemost 2016; doi.org/10.1160/TH16-05-0403

Warfarin-DOAC cohort

DOAC-DOAC cohort

Truven MarketScan Commercial & Medicare supplemental US claimdatabase45,361 newly AC NVAF pts

Major bleeding during treatment with VKAs or DOACs (Perugia and Dresden Registry: 806 cases)

Becattini C et al. Int J Cardiol 2017;227:261-266

New and updated AHA/ASA recommendationson management od spontaneous ICH

Hemphill JC III et al. Stroke 2015;46:2032-2060

Reversal agents for DOACs

Guiseth MP. Am J Health-Syst Pharm 2016;73(10):S5-S13

Emergency treatment of patients experiencing acute ischemic stroke (extending Diener’s expert opinion)

Canavero I et al. Clin Appl Thromb Hemost 2017 (in press)

Paciaroni et al, Stroke 2008

Hemorrhagic transformation

(HI-1)Small petechiaealong the margins of the infarct

(HI-2)More confluent petechiae within the infarcted area but without Space-occupyingeffect

(PH-1)Hematoma in <30%of the infarcted areawith some slight Space-occupyingeffect

(PH-2)Dense hematoma >30% of theinfarcted area with substantial space-occupying effect or as anyhemorrhagic lesion outside the infarcted area

Pathogenesisof spontaneous

and anticoagulation-associated ICH

Charidimou A et al. Front Neurol 2012;3(133):1-13

SVD e rischio di sICH

Grado WML 0-1 2 3 4-8

OR (95%CI) 1.00 1.68 (0.86-3.30) 3.52 (1.80-6.89) 3.96 (1.90-8.27)

N° infarti cerebrali 0 1 2 >=3

OR (95%CI) 1.00 1.97 (1.10-3.54) 2.00 (0.83-4.78) 3.12 (1.31-7.43)

Atherosclerosis Risk in Community Study andCardiovascular Health Study4,872 participants initially free of clinical stroke

Folsom AR et al. Ann Neurol 2012;71:552-559

Grado WML

0, 1 o 2 >=3

Infarto Infarto

Assente Presente Assente Presente

OR (95%CI) 1.00 2.42 (1.17-5.00) 3.19 (1.71-5.96) 4.27 (2.20-8.28)

Risk of recurrence in generalintracerebral hemorrhage

Weimar et al; Cerebrovascular Dis 2011; 32: 283-288

Incidence rate of ischemic and hemorrhagiccomplications during 1-year follow-up in

patients with and without OAC resumption

Kuramatsu JB et al. JAMA 2015;313(8):824-836

19 Germany terziary care centers1176 individuals853 for analysis of hematoma enargement719 for analysis of OAC resumption

The risk of recurrent intracranial bleeding

• Deep hemorrhagefor 1000 anticoagulated patients for 1 year:

- 31 fewer thromboembolic strokes

- 19 additional ICHs

• Lobar hemorrhagefor 1000 anticoagulated patients for 1 year:

- 31 fewer thromboembolic strokes

- 150 additional ICHs

Eckman et al. Stroke 2003

Decision-making process in OAC resumption afterOAC-related intracranial bleeding

Canavero I et al. Clin Appl Thromb Hemost 2017 (in press)