NOACs – concurrent indication for DAPT Triple therapy with concurrent indication for DAPT Paul...

TRIPLE THERAPY,

NOACs with concurrent

indication for DAPT Paul Wright

Lead Cardiac Pharmacist

The Heart, UCLH NHS Foundation Trust

Content

Why consider triple therapy

What we know of triple therapy

Current trials

Practice points

Questions

Why consider triple therapy

Focus on patients with indication for PCI who require

anticoagulation.

Estimated 5-10% of patients with ACS have an indication

for anticoagulants (predominantly AF – less commonly

concurrent LV thrombus, thromboembolic disorders.

Why consider triple therapy

In stent

thrombosis

Stroke

prevention

Why consider triple therapy

In stent

thrombosis

Stroke

prevention

Bleeding

Ischaemic

complications

Why consider triple therapy Is it really necessary?

Anticoagulation for prevention of IST

Limited data

Early data suggested combination of aspirin/ticlopidine less ischaemic

events than aspirin or aspirin/warfarin1

Why consider triple therapy Is it really necessary?

Anticoagulation for prevention of IST

Limited data

Early data suggested combination of aspirin/ticlopidine less ischaemic

events than aspirin or aspirin/warfarin1

Antiplatelets for stroke prevention

Aspirin meta analysis 10-20% RRR P=NS

AVERROES – anticoagulant superior to aspirin2

1ry outcome 1.6% vs. 3.7% equates to RRR 57%

ACTIVE – W stopped early 30% RRR with similar bleeding3

1ry outcome 3.9% vs 5.6%

1 NEJM (1999); 339: 1665-71 2 NEJM (2011); 364:806-17 3 Lancet (2006); 367:1903-12

Why consider triple therapy Other considerations:

CHA2DS2VAS baseline 30% RRR 60% RRR

Score 0 = 0% 0% 0%

Score 1 = 1.3% 0.91% 0.52%

Score 2 = 2.2% 1.54% 0.88%

Score 4 = 4.0% 2.8% 1.6%

Why consider triple therapy Other considerations:

CHA2DS2VAS baseline 30% RRR 60% RRR

Score 0 = 0% 0% 0%

Score 1 = 1.3% 0.91% 0.52%

Score 2 = 2.2% 1.54% 0.88%

Score 4 = 4.0% 2.8% 1.6%

Duration antiplatelets

BMS – 1 month (or more)

DES – 1 year …… but third generation stents being

evaluated for less time

Elective vs. acute PCI

Newer agents – more potent antiplatelets, NOACs, PAR1

What we know of triple therapy

Very little RCT studies undertaken!

Cohort data

VKA and DAPT

Guidance

NICE

ESC

NOACs and DAPT

Crude incidence rates of fatal and nonfatal bleeding according to antithrombotic regimen in

time periods following inclusion.

Lamberts M et al. Circulation. 2012;126:1185-1193

Copyright © American Heart Association, Inc. All rights reserved.

ESC survey 2014 Europace (2014) 16, 293–298

ESC survey 2014 Europace (2014) 16, 293–298

WOEST Lancet (2013); 381:1107-15

Comparing DAT to Triple therapy

Indication for OAC and PCI

High risk of bleeding, age >80

OAC + clop 75 vs. OAC + clop 75 + aspirin 80

1 year follow up (min 1month BMS, 1 year DES)

1ry end point – bleeding events (TIMI criteria)

2ry end points – MACE, all individual

WOEST: Primary End point: Total number of bleeding

events (TIMI criteria) Lancet (2013); 381:1107-15

WOEST: Secondary End points: Break down of bleeding

events (TIMI criteria) Lancet (2013); 381:1107-15

WOEST: Secondary End points: MACE – inc. death, MI,

TVR, Stroke, ST Lancet (2013); 381:1107-15

Other VKA trials ISAR – TRIPLE

6 week vs 6 month clop in DES and AF

600 pts

Presented at TCT awaiting publication

Similar incidence of ischaemic events

Similar incidence of major bleeding

Other VKA trials ISAR – TRIPLE

6 week vs 6 month clop in DES and AF

600 pts

Presented at TCT awaiting publication

Similar incidence of ischaemic events

Similar incidence of major bleeding

Anticoagulation in Stent Intervention (MUSICA-2)

CHADS < 2

ASA 300mg / clop vs. VKA / clop / ASA 100mg

Aim 304 patients undergoing PCI with AF

Completion due Dec 2015

ESC 2010 AF recommendations European Heart Journal (2010) 31, 2369–2429

Data with NOACs?

APPRAISE-2 N Engl J Med 2011;365:699-708.

Apixaban 5mg bd when added following ACS and DAPT

Stopped early due to increase major bleed with no

counterbalance in reduction of ischaemic events

RE-DEEM European Heart Journal doi:10.1093/eurheartj/ehr113

Dabigatan vs. placebo in patients th ACS on DAPT –

phase II study

Dose ranging from 50, 75, 110 and 150mg bd

ATLAS ACS 2-TIMI 51 NEJM 2012 366(1):9-19

Recent ACS (50% STEMI, 25% NSTEMI, 25% UA)

15,526 patients to riva 2.5 bd, 5mg bd, placebo.

Enrolment with 7 days after admission for ACS

Mean duration 13 months (up to 31 months)

1ry end point, composite of MACE

ATLAS ACS 2-TIMI 51 NEJM 2012 366(1):9-19

ATLAS ACS 2-TIMI 51 NEJM 2012 366(1):9-19

NNT 63 NNT 53

NNT 72 NNT - NA

ATLAS ACS 2-TIMI 51 NEJM 2012 366(1):9-19

Future trials with NOACs

Evaluation of Dual Therapy With Dabigatran vs. Triple

Therapy With Warfarin in Patients With AF That

Undergo a PCI With Stenting (REDUAL-PCI)

110mg dabigatran etexilate b.i.d. plus clopidogrel or ticagrelor

(110mg Dabigatran Etexilate Dual Antithrombotic Therapy (DE-DAT))

150mg dabigatran etexilate b.i.d. plus clopidogrel or ticagrelor

(150mg DE-DAT)

Triple Antithrombotic Therapy (TAT) combination of warfarin plus

clopidogrel or ticagrelor plus ASA <= 100mg q.d. (warfarin-TAT)

Patients with Atrial Fibrillation that undergo a PCI with stenting

(elective or due to an ACS).

The study aims to show non-inferiority of both doses of DE-DAT

when compared to Warfarin-TAT in efficacy and safety.

Study completion July 2017

A Study Exploring Two Strategies of Rivaroxaban and One

of Oral Vitamin K Antagonist in Patients With Atrial

Fibrillation Who Undergo Percutaneous Coronary

Intervention (PIONEER AF-PCI)

Rivaroxaban 2.5 mg tablet twice daily plus low-dose aspirin and clopidogrel (or prasugrel or ticagrelor) followed by rivaroxaban 15 mg tablet (or 10 mg for subjects with moderate renal impairment) once daily plus low-dose ASA for 12 months

Rivaroxaban 15 mg (or 10 mg for subjects with moderate renal impairment) once daily plus clopidogrel (or prasugrel or ticagrelor) for 12 months

Dose-adjusted VKA (INR 2.0 to 3.0) plus low-dose ASA, and clopidogrel (or prasugrel or ticagrelor) followed by dose-adjusted VKA once daily (target INR 2.0 to 3.0 or 2.0 to 2.5 at the investigator discretion) plus low-dose ASA for 12 months

DAPT for 1,6 or 12 months

Primary purpose of this study is to evaluate safety

Study completion August 2016

Final considerations Weigh up bleeding vs ischaemic risk

Elective vs acute treatment (longer duration?)

Consequence of treatment failure – IST, stroke

More potent antiplatelets – prasugrel, ticagrelor

What combination and duration of TT or DT

Moving towards NOACs

Ease of administration

VKA bleeding apparent in first 3 months

What dose of NOAC with antiplatelets

………..treat the patient

Case 1 Mr A Rhythm

42yr, STEMI, DES to LAD

PMH – angina, diabetes, pAF (2

unsuccessful ablations)

SH – smokes, moderate EtOH

Drug Hx – Rivaroxaban

20mg od Atorvastatin 40mg

od Amlodipine 5mg od

Metformin 1g bd

Ramipril 2.5mg od

Questions

Any other

considerations?

Initial antithrombotic

strategy

What duration of

antithrombotics

Case 1 Stroke vs IST

CHA2DS2VASc = 2

2.2% per yr

0.18% per month

STEMI – trust policy ticagrelor

Bleeding

HAASBLED = 0

Case 1 Stroke vs IST

CHA2DS2VASc = 2

2.2% per yr

0.18% per month

STEMI – trust policy ticagrelor

Bleeding

HAASBLED = 0

OPTIONS:

Aspirin Clopidogrel Warfarin

Ticagrelor NOAC

Prasugrel (or none!)

DURATION? 1, 3, 6, 12 months?

Case 1 Stroke vs IST

CHA2DS2VASc = 2

2.2% per yr

0.18% per month

STEMI – trust policy ticagrelor

Bleeding

HAASBLED = 0

OPTIONS:

Aspirin Clopidogrel Warfarin

Ticagrelor NOAC (what dose?)

Prasugrel (or none!)

DURATION? 1, 3, 6, 12 months?

Case 2 Mrs A Fibrillation

67yr, NSTEMI, BMS to LAD, RCA

PMH – previous stroke, AF,

previous GI bleed 8/52 ago, HTN,

LVEF 30%

Drug Hx –

Warfarin (INR 2-3)

Atorvastatin 20mg od

Digoxin 250mcg od

Ramipril 5mg bd

Bisoprolol 5mg od

Spironolactone 25mg od

Lansoprazole 30mg od

Questions

Any other

considerations?

Initial antithrombotic

strategy

What duration of

antithrombotics

Case 2 Stroke vs IST

CHA2DS2VASc =6

9.8% per yr

0.82% per month

NSTEMI – risk assess CRUSADE / GRACE

Bleeding

HAASBLED = 4

Case 2 Stroke vs IST

CHA2DS2VASc =6

9.8% per yr

0.82% per month

NSTEMI – risk assess CRUSADE / GRACE

Bleeding

HAASBLED = 4

OPTIONS:

Aspirin Clopidogrel Warfarin

Ticagrelor NOAC

Prasugrel (or none!)

DURATION? 1, 3, 6, 12 months?

Case 2 Stroke vs IST

CHA2DS2VASc =6

9.8% per yr

0.82% per month

NSTEMI – risk assess CRUSADE / GRACE

Bleeding

HAASBLED = 4

OPTIONS:

Aspirin Clopidogrel Warfarin

Ticagrelor NOAC

Prasugrel (or none!)

DURATION? 1, 3, 6, 12 months?

Questions