UN DECENNIO DI INNOVAZIONE CON GLI ANTICOAGULANTI … · Giuseppe Di Pasquale Disclosures • Member of the Steering Committee of the RELY, PALLAS, and GLORIAAF • Member of Advisory

UN DECENNIO DI INNOVAZIONE

CON GLI ANTICOAGULANTI ORALI DIRETTI:

NUOVE PROSPETTIVE NELLE APPLICAZIONI CLINICHE

12° Meeting CardioLucca 2018

“IL labirinto cuore tra scienza e assistenza”

Lucca, 23 Febbraio 2018

Giuseppe Di Pasquale

Direttore Dipartimento Medico ASL Bologna

Direttore Unità Operativa Cardiologia

Ospedale Maggiore, Bologna

Giuseppe Di Pasquale Disclosures

• Member of the Steering Committee of the RELY, PALLAS, and

GLORIA AF

• Member of Advisory Board of Dabigatran,

Rivaroxaban, Apixaban, Dronedarone, Edoxaban

• Consulting fees / honoraria

Boehringer Ingelheim, Bayer AG, Sanofi Aventis

BMS / Pfizer, Daiichi Sankyo

FA valvolare

November 7, 2017

Breithardt G at al. Eur Heart J 2014

Avezum A et al. Abstract 4384, ESC Congress 2013

Ezekowitz et al. Circulation 2016;134:589-598

Renda G at al. Abstract ACC 2016

JACC 2017;69:1363-71

Renda G et al. JACC 2017;69:1363-71

Lip GYH et al.

Europace November 1, 2017

EHRA Consensus Document

Circulation 2017;135:1273-75

Carnicelli AP et al. Circulation 2017;135:1273-75

Lip GYH et al. Europace , November 1, 2017

EHRA Consensus Document

Bioprostheses

NAO: Quali spazi futuri?

NOACs : Future Perspectives

New Frontiers

NOACs vs LAAO▪

HF with SR▪

TAVI▪

ESUS▪

Cardiopatia ischemica cronica▪

WATCHMAN LAA Closure Device in situ

3000838-18

Dati meta-analitici di outcome dai 4 RCT di confronto tra NAO e

VKA e dai 2 studi RCT di confronto tra LAAO e warfarin

Patti G et al, Giornale Italiano di Cordiologia Invasiva, 2015;4:36-40

Left Atrial Appendage Occlusion vs NOACs

Ongoing Studies

▪ LAA Closure vs Novel Anticoagulation Agents in AF

(PRAGUE 17): apixaban vs Watchman; estimated enrollment 400 pts

▪ Evaluation of Watchman LAAO Device in Patients with

AF versus Rivaroxaban : estimated enrollment 200 pts

▪ Safety and Efficay of LAA Closure vs Antithrombotic

Treatment in Patients with AF Undergoing DES

Implantation due to Complex CAD: dabigatran plus

aspirin/clopidogrel vs ACP; estimated enrollment 300 pts


New Frontiers

NOACs vs LAAO▪

HF with SR▪

TAVI▪

ESUS▪

Cardiopatia ischemica cronica▪

Kumar G et al J Stroke Cerebrovasc Dis 2013; 22: 1279-87

Warfarin vs aspirin 95% CI p pooled RR

Mortality 1 0.88-1.13 ns

Stroke 0.59 0.41-0.85 0.004

Major bleeds 1.95 1.37-2.76 0.0001

ICH 2.17 0.76-6.24 ns

NNT 61

NNH 34

www.clinicaltrials.gov/ct2/show/NCT01877915

Objective: demonstrate that Rivaroxaban is superior to placebo in subjects with chronic heart failure (HF) and significant coronary artery disease (CAD), who are receiving standard care, following a recent hospitalization for exacerbation of HF

15–45-day follow-up

Rivaroxaban 2.5 mg BID(single or dual antiplatelet therapy)

Placebo (single or dual antiplatelet therapy)

N: 5000

R

Global treatment end date*

EOS visit

1:1

Randomized, double blind

Primary Endpoints:Efficacy• : Composite MI, stroke, all-cause deathSafety• : Fatal bleeding, critical organ bleeding with potential for permanent disability

Study Population:post exacerbation of chronic HF plus significant CAD

6 – 30 months

FPFV: Q3 2013LPLV: ~Q2 2016


New Frontiers

▪ NOACs vs LAAO

▪ HF with SR

▪ TAVI

▪ ESUS

▪ Cardiopatia ischemica cronica

Evoluzione della valvola Corevalve (A) e Sapien (B)

Europace 2017;19:1757-58

Current post-TAVI Antithrombotic Management RCTs

N°Pts

Antithrombotic management

ARTE 155

ASA for 6 months

vs

ASA for 6 months plus Clopidogrel for 3 months

POPular TAVI 1010

ASA or OAC for 12 months

vs

ASA or OAC for 3 months plus Clopidogrel for 12 months

AUREA 124

ASA plus Clopidogrel for 3 months

vs

OAC for 3 months

AVATAR 170

OAC for 12 months

vs

OAC plus antiplatelet therapy for 12 months

GALILEO 1520

Rivaroxaban for 25 months plus ASA for 3 months

vs

ASA for 25 months plus clopidogrel for 3 months

ATLANTIS 1505- Indication to OAC: Apixaban vs OAC for 13 months

- No indication to OAC: Apixaban vs SAPT/DAPT for 13 months

J Am Coll Cardiol Intv 2017;10:66-74

J Am Coll Cardiol Intv 2017;10:66-74

Windecker S. et al. Am Heart J 2017;184:81-7


New Frontiers

▪ NOACs vs LAAO

▪ HF with SR

▪ TAVI

▪ ESUS


Lancet Neurol 2014;13:429-38

Distribution of ischaemic stroke subtypes in North American and European studies

Ntaios et al. Stroke 2015;46:2087-93

ESUS: 5-years stroke recurrence

Ongoing ESUS Trials with NOACs

Ongoing RCTs on ESUS patients Variables RE-SPECT NAVIGATE ATTICUS

Type of

RCT

Double-blind Double-blind Open-label

Subjects patients with

recent ESUS

patients with

recent ESUS

ESUS plus “suggestive

factors for cardiac

embolism”: LA size >45mm;

LAA spontaneous echo

contrast; LAA flow velocity

<0.2m/s; atrial high-rate

episodes; CHA2DS2Vasc >4;

patent foramen ovale

N° of pts. 6000 7060 500

Primary

efficacy

recurrent stroke recurrent stroke

and systemic

embolism

new ischemic lesion on MRI

after 12 months compared

with baseline MRI

Medicatio

ns

Dab 110 or 150

b.i.d vs Aspirin 100

mg

Riva15 mg vs

Aspirin 100 mg

Apixaban 5mg b.i.d. vs

Aspirin 100mg

This decision is based on the recommendation of the study’s

Independent Data Monitoring Committee (IDMC) as the trial

showed comparable efficacy between rivaroxaban and the

standard of care, aspirin, and little chance of rivaroxaban

showing an overall benefit versus aspirin if the study were to

be completed. While bleeding rates were very low overall and

within the expected range, an increase in bleeding was

observed in the rivaroxaban arm compared to aspirin.


New Frontiers

▪ NOACs vs LAAO

▪ HF with SR

▪ TAVI

▪ ESUS


A Dual Pathway Approach Targeting Chronic Patients

with CAD or PAD was Investigated in COMPASS

Objective: To determine the efficacy and safety of rivaroxaban, vascular dose of rivaroxaban plus aspirin or aspirin alone for reducing the risk of MI, stroke and cardiovascular death in CAD or PAD

Antithrombotic investigations* were stopped 1 year ahead of expectations in Feb 2017 due to

overwhelming efficacy in the rivaroxaban 2.5 mg bid + aspirin arm

Rivaroxaban 5.0 mg bid

Aspirin 100 mg od

Rivaroxaban 2.5 mg bid + Aspirin 100 mg od

30-day

washout

period

30-day run-in,

aspirin 100 mg

Final

follow-up

visit

R

Final

washout

period visit

1:1:1

N=27,395

Population:

Chronic

CAD (91%)

PAD (27%)

*Patients who were not receiving a proton pump inhibitor (PPI) were randomized to pantoprazole or placebo (partial factorial design); the PPI

pantoprazole component of the study is continuing; data will be communicated once complete

1. Eikelboom JW et al. N Engl J Med 2017; DOI: 10.1056/NEJMoa1709118;

2. Bosch J et al. Can J Cardiol 2017;33(8):1027–1035

Average follow-up: 23 months at early termination of study

Factorial design

± pantoprazole*

PADCAD

Key Baseline Characteristics Are in Line With Those

Usually Seen in Patients With Chronic CAD or PAD

Characteristic Rivaroxaban 2.5 mg

bid + aspirin 100 mg

N=9152

Rivaroxaban 5 mg bid

N=9117

Aspirin 100 mg

N=9126

Age, years 68 68 68

Blood pressure, mmHg 136/77 136/78 136/78

Total cholesterol, mmol/L 4.2 4.2 4.2

CAD, % 91 90 90

PAD, % 27 27 27

Diabetes, % 38 38 38

Lipid-lowering drugs, % 90 90 89

ACE inhibitors/ARB, % 71 72 71

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker

*Excluding <7 days before randomization

Eikelboom JW et al. N Engl J Med 2017; DOI: 10.1056/NEJMoa1709118

PADCAD

Patients in COMPASS Were Receiving

High Standard of Care

Baseline medication Total

N=27,395

n (%)

ACE inhibitor/angiotensin receptor blocker 19,518 (71.2)

Calcium channel blocker 7269 (26.5)

Diuretic 8139 (29.7)

Beta-blocker 19,184 (70.0)

Lipid-lowering agent 24,601 (89.8)

NSAID 1470 (5.4)

Non-study PPI 9798 (35.8)


PADCAD

Dual Pathway Inhibition with Rivaroxaban Vascular Dose

2.5 mg bid + Aspirin Reduced CV Death, Stroke and MI

*Rates as at mean follow up of 23 months


MACE* % HR (95% CI) p-value

Aspirin 100mg OD 5.4 - -

Rivaroxaban 5mg BID 4.9 0.90 (0.79-1.03) 0.12

Rivaroxaban 2.5mg BID +

Aspirin 100 mg OD4.1 0.76 (0.66-0.86) <0.001

Cu

mu

lati

ve

in

cid

en

ce

(%

)

0

2

4

6

8

10

0 1 2 3

Rivaroxaban 2.5mg bid + Aspirin 100mg od

Rivaroxaban 5mg bid

Aspirin 100mg od

Number at risk

Aspirin 100mg od 9126 7808 3860 669

Riva 5mg bid 9117 7824 3862 670

Riva 2.5mg bid +

Aspirin 100mg od9152 7904 3912 658

Year

PADCAD

Dual Pathway Inhibition with Rivaroxaban 2.5 mg bid + Aspirin:

Significantly Reduced CV Events by 24% Versus Aspirin

Outcomes, n (%) Rivaroxaban

2.5 mg bid +

aspirin 100 mg

N=9152

Aspirin

100 mg

N=9126

Rivaroxaban 2.5 mg bid +

aspirin 100 mg vs aspirin 100 mg

HR (95% CI) p-value

CV death, stroke,

or MI379 (4.1) 496 (5.4) 0.76 (0.66–0.86) <0.001

CV death 160 (1.7) 203 (2.2) 0.78 (0.64–0.96) 0.02

Stroke 83 (0.9) 142 (1.6) 0.58 (0.44–0.76) <0.001

MI 178 (1.9) 205 (2.2) 0.86 (0.70–1.05) 0.14

Outcomes, n (%)Rivaroxaban

5 mg bid

N=9117

Rivaroxaban 5 mg bid vs

aspirin 100 mg

HR (95% CI) p-value

CV death, stroke,

or MI448 (4.9) 0.90 (0.79–1.03) 0.12

CV death 195 (2.1) 0.96 (0.79–1.17) 0.69

Stroke 117 (1.3) 0.82 (0.65–1.05) 0.12

MI 182 (2.0) 0.89 (0.73–1.08) 0.24


PADCAD

Bleeding Rates Increased but Low with Rivaroxaban

Vascular Dose 2.5 mg bid + Aspirin Versus Aspirin Alone

Outcome

Rivaroxaban

2.5 mg bid

+ aspirin

N=8313

Rivaroxaban

5 mg bid

N=8250

Aspirin

N=8261

Rivaroxaban

2.5 mg bid + aspirin

vs aspirin

Rivaroxaban

5 mg bid

vs aspirin

N (%) N (%) N (%)HR

(95% CI)p-value

HR

(95% CI)p-value

Major bleeding 263 (3) 236 (3) 158 (2)1.66

(1.37–2.03)<0.0001

1.51

(1.23–1.84)<0.0001

Fatal 14 (<1) 12 (<1) 9 (<1)1.55

(0.67–3.58)0.30

1.33

(0.56–3.16)0.51

ICH 19 (<1) 32 (<1) 19 (<1)0.99

(0.52–1.87)0.98

1.69

(0.96–2.99)0.065

Critical organ 36 (<1) 42 (1) 25 (<1)1.42

(0.85–2.36)0.18

1.70

(1.04–2.79)0.033

Other 194 (2) 150 (2) 105 (1)1.85

(1.46–2.34)<0.0001

1.44

(1.12–1.84)0.0041

Connolly SJ et al, Lancet 2017; doi:10.1016/S0140-6736(17)32816-7

CAD

No significant increase in critical organ bleeding

including intracranial or fatal bleeding

Net Clinical Benefit: 20% RRR with Rivaroxaban

2.5 mg bid + Aspirin Versus Aspirin

Definition: composite of CV death, stroke, MI, fatal bleeding or

symptomatic bleeding into a critical organ

In other words, net clinical benefit represented the composite of fatal •

and non-fatal events of irreversible harm

Outcome Rivaroxaban

2.5 mg bid +

aspirin

100 mg

N=9152

Aspirin

100 mg

N=9126

Rivaroxaban 2.5 mg bid +

aspirin 100 mg

vs aspirin 100 mg

HR (95% CI) p-value

Net clinical

benefit431 (4.7%) 534 (5.9%) 0.80 (0.70–0.91) <0.001


PADCAD

Documents

UN DECENNIO DI INNOVAZIONE CON GLI ANTICOAGULANTI … · Giuseppe Di Pasquale Disclosures • Member of the Steering Committee of the RELY, PALLAS, and GLORIAAF • Member of Advisory