Marco Botta

S.C. Cardiologia

Ospedale San Paolo di Savona

NAO, Fibrillazione Atriale e Sindromi

Coronariche Acute: luci ed ombre

marcobotta.mb@gmail.com

… un po’ di luce …. ancora molte ombre …

ACSPCI (DES – BMS)

Coronary Ischemia

AFDVTPELV thrombus(Mechanical) valves

Stroke

Condition

Aim :

BACKGROUND

Coronary IschemiaStent thrombosis

DAPT better than OAC

1 – 6 – 12 months

StrokeSystemic embolism

OAC better than DAPT

Sometimes lifelong

Aim :Prevention

Evidence

Duration

Condition Drugs Duration

1 year

1 year

1 month

RecommandationEvidence Level

I A

I A (B)

I A (B)

DAPTNSTEMI

STEMI

Elective BMS

Recent GUIDELINES

1 month6 months

I A (B)I A (B)

VKANOACS

LifelongI A

Elective BMSElective DES

AF

LOV 2014

• Nearly 10-30% of patients with acute coronary syndrome (ACS) have AF.

• Anticoagulated patients with AF presenting with an ACS or with chronic ischaemic

Editorial FocusAntithrombotic therapy in atrial fibrillation and st ent implantation: treatment or

threats by the use of triple or dual antithrombotic therapy.

Francisco Marín, Kurt Huber, Gregory Y. H.

• Anticoagulated patients with AF presenting with an ACS or with chronic ischaemicheart disease undergoing percutaneous coronary intervention (PCI) with stent implantation represent a complex management cohort, especially from the concomitant use of dual antiplatelet therapy required after stent implantation, leading to triple therapy (TT).

• In these patients, one has to balance the risk of stroke (from AF), recurrent cardiac ischemia (if ACS), stent thrombosis and serious bleeding.

Thrombosis and Haemostasis 110.4/2013

CHA2DS2-VASc Score

HAS-BLED Risk Score

ESC Guidelines. European Heart Journal 2010; 31

HAS-BLED >= 3: indicates "high risk" and some caution and regular review of the patient is needed

The Pharmacology Confusion…

�Both ischemic complications and bleeding complications have significant impact on clinical outcome.

�The most effective antithrombotic treatment will

Thrombosis VS Bleeding

be associated with increase in bleeding complications.

�The safest antithrombotic treatment in terms of bleeding will be associated with increase in ischemic complications.

How to square the circle ?

ANTITHROMBOTIC THERAPY

Antipiastrinici

Orali:-Asa-Ticlopidina-Clopidogrel-Prasugrel-Ticagrelor

Eparine

-Eparine bpm-Fondaparinux-Eparina sodica

Anticoagulanti Orali

-Warfarin-Acenocumarolo

-Dabigatran-Rivaroxaban-Apixaban

Bivalirudina-Ticagrelor

Endovenosi:-Asa-Inibitori IIb-IIIaAbciximabEptifibatideTirofibam

-Apixaban

Fibrinolitici

-rtPA-Tenecteplase

Double and Triple Therapy Antipiastrinici Orali + Anticoagulanti Orali

Quale OAC e Quale Terapia

Antipiastrinica…

… Dati su Double o Triple Therapy… Dati su Double o Triple Therapy

con Warfarin

The WOEST Trial: First randomised trial comparing two regimens with and without aspirin in patients on oral anticoagulant therapy undergoing coronary stenting

Willem Dewilde, Tom Oirbans, Freek Verheugt, Johannes Kelder, Bart De Smet, Jean-Paul Herrman, Tom Adriaenssens, Mathias Vrolix,

WOEST ESC, Hotline III, Munchen, August 28th, 2012

|

De Smet, Jean-Paul Herrman, Tom Adriaenssens, Mathias Vrolix, Antonius Heestermans, Marije Vis, Saman Rasoul, Kaioum

Sheikjoesoef, Tom Vandendriessche, Carlos Van Mieghem, Kristoff

Cornelis, Jeroen Vos, Guus Brueren, Nicolien Breet and Jurriën ten Berg

The WOEST Trial= What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing

(clinicaltrials.gov NCT00769938)

Study Design-2

1:1 Randomisation:

Double therapy group:

OAC + 75mg Clopidogrel qd

1 month minimum after BMS

Triple therapy group

OAC + 75mg Clopidogrel qd + 80mg Aspirin qd

1 month minimum after BMS

WOEST

|

1 month minimum after BMS

1 year after DES

1 month minimum after BMS

1 year after DES

Follow up: 1 year

Primary Endpoint: The occurence of all bleeding events (TIMI criteria )

Secondary Endpoints:- Combination of stroke, death, myocardial infarction , stent thrombosis andtarget vessel revascularisation

- All individual components of primary and secondary endpoints

Primary Endpoint: Total number of TIMI bleeding eve nts

Cum

ulat

ive

inci

denc

e of

ble

edin

g

30 %

40 %

50 % Triple therapy groupDouble therapy group 44.9%

19.5%

WOEST

|

Days

Cum

ulat

ive

inci

denc

e of

ble

edin

g

0 30 60 90 120 180 270 365

0 %

10 %

20 %

284 210 194 186 181 173 159 140n at risk: 279 253 244 241 241 236 226 208

19.5%

p<0.001

HR=0.36 95%CI[0.26-0.50]

Secondary Endpoint (Death, MI,TVR, Stroke, ST)

Cum

ulat

ive

inci

denc

e

10 %

15 %

20 %17.7%

11.3%

Triple therapy groupDouble therapy group

WOEST

Days

Cum

ulat

ive

inci

denc

e

0 30 60 90 120 180 270 365

0 %

5 %

284 272 270 266 261 252 242 223n at risk: 279 276 273 270 266 263 258 234

p=0.025

HR=0.60 95%CI[0.38-0.94]

All-Cause Mortality

Cum

ulat

ive

inci

denc

e of

dea

th

5 %

7.5 %

6.4%

HR=0.39 95%CI[0.16-0.93]

p=0.027

Triple therapy groupDouble therapy group

WOEST

Days

Cum

ulat

ive

inci

denc

e of

dea

th

0 30 60 90 120 180 270 365

0 %

2.5 %

284 281 280 280 279 277 270 252n at risk: 279 278 276 276 276 275 274 256

2.6%

Trial’s Conclusions1. First randomized trial to address the optimal antiplatelet therapy in patients on OAC

undergoing coronary stenting

2. In this study which was specifically designed to detect bleeding events, the bleeding

rate was higher than expected

WOEST

|

3. Primary endpoint was met: OAC plus clopidogrel causes less bleeding than triple

antithrombotic therapy, but now shown in a randomized way

4. Secondary endpoint was met: with double therapy there is no excess of

thrombotic/thromboembolic events: stroke, stent thrombosis, target vessel

revascularisation, myocardial infarction or death

5. Less all-cause mortality with double therapy

ISAR Triple - Am Heart J - TCT 2014

614 pz. Dopo impianto di DES in ASA + Warfarin + 6 wee k or 6 month of Clopidogrel (307 and 307)

Benefit and Safety With Triple Therapy Versus Dual Therapies

Triple therapy (oral anticoagulant [OAC] plus aspirin plus clopidogrel [dotted line]) isused as reference (hazard ratio ¼1.00).

Orange circles indicate OAC plus clopidogrel

Yellow circles indicate OAC plus aspirin

Green circles indicate aspirin plus clopidogrel. MI ¼ myocardial infarction.

In real-life AF patients with indication for multipleantithrombotic drugs after MI/PCI, OAC andClopidogrel was equal or better on both benefit andsafety outcomes compared to triple therapy.

Warfarin and New P2Y 12: Pochi Dati…

In both

PLATO (Ticagrelor)and

TRITON-TIMI 38 (Prasugrel)Studies

Patients were excluded from enrollment

if receiving VKA

Warfarin and New P2Y 12: Pochi Dati…

Warfarin and New P2Y 12: Ongoing Trial…

CONCLUSIONS

The efficacy of triple therapy (VKA, aspirin, and clopidogrel) in AF

patients who need to undergo PCI with stent placement has

never been proven, but this strategy increases bleeding risk never been proven, but this strategy increases bleeding risk

significantly. New evidence, including a randomized controlled

trial and a real-life nationwide registry of more than 12,000

patients, showed the great potential of the combination of VKA

and clopidogrel without aspirin to improve clinical outcomes in

comparison with triple therapy.

Therefore, VKA combined with clopidogrel seems to be a

reasonable alternative to triple therapy in patients on long-

term VKA who undergo PCI and stenting.

Quale OAC e Quale Terapia

Antipiastrinica …

… Dati su Double o Triple Therapy… Dati su Double o Triple Therapy

con New Oral Anticoagulants

ASA CLOPIDOGRELASA+

CLOPIDOGREL

40% 6% 4%

Trattamento Antiaggregante nei Trials sui NAO

37% n.d.

31% 2%

SUBGROUP RELY

SUBGROUP RELY

SUBGROUP ROCKET-AF

SUBGROUP ARISTOTLE

RE-DEEM Trial Conclusions

• The study was not powered to demonstrate an efficac y difference in cardiovascular death, nonfatal myocardial infarc tion or non haemorragic stroke

• A dose-dependent increase in clinically relevant bl eeding events was observed, with highest rates whit the dose of 1 10 and 150 mg of Dabigatran

ATLAS ACS 2 TIMI 51 Conclusions: Compared with placebo, Rivaroxaban

(2.5 or 5 mg bid) on top of ASA or ASA plus clopidogrel showed:

– Significant reductions in the rates of death, MI , and stroke

– Benefits in all types of ACS patients (UA, NSTEMI and STEMI )

– More than a 30% reduction in risk of both CV and all-cause mortality

(2.5 mg bid)

N Engl J Med 2011

(2.5 mg bid)

– No increase in fatal bleeding and fatal ICH

– A non-bleeding safety profile similar to placebo

The addition of anticoagulation with rivaroxaban may represent a new

treatment strategy in patients after recent ACS

ApixabanApixaban with antiplatelet therapy with antiplatelet therapy

after acute coronary syndromeafter acute coronary syndrome

The APPRAISEThe APPRAISE--2 trial2 trial

NEJM 2011; 365:699

Cardiac death, MI or stroke occurred in 7.5% of patients on apixaban and 7.9% of patients on placebo

Major bleeding occurred in 1.3% of patients on apixaban and 0.5% of patients on placebo

Conclusions: Apixaban increased major bleeding event s but did not significantly reduce recurrent ischemic events

No Data on New P2Y12

PRASUGRELTICAGRELOR

In patient with a recent acute coronary syndrome, the additi on of anew oral anticoagulant to antiplatelet therapy results in a modestreduction in cardiovascular events but a substantial incre ase inbleeding, most pronounced when new oral anticoagulants arecombined with dual antiplatelet therapy.

PIONEER AF-PCI: study design

Open label, randomized, controlled, multi-center study exploring

two treatment strategies of RivaroxabanRivaroxaban and a dose adjusted oral

VKA treatment strategy in patients with AF who undergo PCI

Rivaroxaban 15 mg OD*#+ clopidogrelN= 2100

Ongoing Trial

3232Clinicaltrials.gov: NCT01830543

Study population: patients with paroxysmal, persistent or

permanent AF

End of

treatment

(12 months)

*: reduced to 10 mg OD in patients with CrCl 30-50 ml/min#: first dose administered 72-96 h after sheath removal§: first dose administered 12-72 h after sheath removal

1:1:1

R

Rivaroxaban 2.5 mg BID§

+DAPTPCI (with

stent placeme

nt)

VKA (target INR 2-3)§

+DAPT

Rivaroxaban 15 mg OD*

+ low dose ASA

VKA + low dose ASA

Intended DAPT duration

Of 1,6 or 12 months

The RE-DUAL PCI™ trial (Randomized Evaluation of Dual Therapy with DabigatranDabigatran vs. Triple Therapy Strategy with Warfarin in Patients with NVAF that have undergone PCI with Stenting)

Patients undergoing PCI

Dabigatran (150 mg or 110 mg twice daily) + single antiplatelettherapy with a P2Y12 protein inhibitor therapy with a P2Y12 protein inhibitor compared to warfarin + two antiplatelet agents

to assess clinically relevant bleeding and thrombotic events (combined rate of death, myocardial infarction and stroke)

Le attuali RACCOMANDAZIONI ….

Eur Heart J Sept 2014

Eur Heart J Sept 2014Se N OAC: Dabigatran 110 mg, Rivaroxaban 15 mg, Apixaban 2,5 mg

Recommended antithrombotic strategies following coronary stenting in patients

with atrial fibrillation at moderate-to-high thromboembolic risk

(in whom OAC therapy is required)

OAC and Clopidogrel may be an alternative

2014 ESC/EACTS

GUIDELINES ON

MYOCARDIAL

REVASCULARIZATION

OAC and Clopidogrel may be an alternative

OAC and Clopidogrel may be an alternative

ESC-EHRA-EAPCI-ACCA-HRS-

APHRS

Eur Heart J Aug 2014

JOINT CONSENSUS DOCUMENT

Antithrombotic Management in Atrial Fibrillation patients with ACS/PCI

Eur Heart J Aug 2014

2014 Executive Summary AHA/ACC/HRS Atrial Fibrillation Guidelines

Terapia Anticoagulante e Terapia Antiaggregante … dopo SCA e PCI

• Non esiste una controindicazione all’impiego dei NAO nei pazi enticon patologia atero-trombotica coronarica o che si sottopo ngono aprocedure di rivascolarizzazione per via percutanea

• Non e’ stata documentata una reale interazione sfavorevole i ntermini di efficacia e sicurezza tra i NAO e gli Antiaggreganti (Asa eClopidogrel); e’ riportato solo un incremento dei sanguina mentinell’associare i NAO alla doppia antiaggregazione

CONCLUSIONS & TAKE HOME MESSAGES - 1

nell’associare i NAO alla doppia antiaggregazione

• Il parere degli esperti nei Documenti di Consenso e nelle Lin eeGuida propende per una limitazione all’impiego protratto di unatriplice terapia antitrombotica

• 1 solo studio randomizzato “valida” l’associazione di Warfari n eClopidogrel; i sottogruppi dei 3 principali studi sui NAO “li indicanopiù sicuri” di Warfarin anche in corso di terapia antiaggreg ante

• Non e’ ancora noto l’impatto sulle problematiche trombotic he edemorragiche di questi pazienti in ogni associazione che preve da inuovi farmaci antipiastrinici e i nuovi anticoagulanti ora li

TERAPIA ANTITROMBOTICA

PAZIENTE CON FIBRILLAZIONE ATRIALE

E “ACS/STABLE CAD” SOTTOPOSTO A PCI

…Prima della PCI … Post PCI …

Single Therapy

CHA2DS2-VASc Score

HAS-BLED Score

Clinical Setting : ACS o Stable CAD

Timing (1 - 6 > 12 mesi)

CONCLUSIONS & TAKE HOME MESSAGES - 2

CHA2DS2-VASc Score

HAS-BLED Score

…Terapia lifelong

N (OAC)

Double Therapy

Triple Therapy

ASA + Clopidogrel+ Warfarin

Clopidogrel+

WarfarinSingle Therapy

Clinical Setting : ACS o Stable CAD

PCI Bare Metal Stent o Drug Eluting Stent

N (OAC)

INR 2-2,5

ASA o Clopidogrel+

NAO

as short aspossible

Singolo Paziente

AREE GRIGIE…

Double Therapy (ASA o Clopidogrel) + NAO…

Triple Therapy (ASA + Clopidogrel) + NAO…

CONCLUSIONS & TAKE HOME MESSAGES - 3

Good Daily Clinical Practice

Trials Clinici

Linee Guida

Singolo Paziente

“Buon Senso Clinico”

Polipatologia

Nuovi Inibitori P2Y 12 (Prasugrel e Ticagrelor) + Warfarin e/o NAO…

BMS o Nuovi DES …

Se SCA in NAO si prosegue NAO o si passa a Warfarin …

Anziani Fragili, con IRC avanzata e FA e/o SCA …

GRAZIE PER GRAZIE PER

L’ATTENZIONEL’ATTENZIONE