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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