TRIPLE THERAPY, NOACs with concurrent indication for DAPT. Paul Wright Lead Cardiac Pharmacist The Heart, UCLH NHS Foundation Trust

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1 TRIPLE THERAPY, NOACs with concurrent indication for DAPT Paul Wright Lead Cardiac Pharmacist The Heart, UCLH NHS Foundation Trust

2 Content Why consider triple therapy What we know of triple therapy Current trials Practice points Questions

3 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.

4 Why consider triple therapy In stent thrombosis Stroke prevention

5 Why consider triple therapy Bleeding In stent thrombosis Stroke prevention Ischaemic complications

6 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/warfarin 1

7 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/warfarin 1 Antiplatelets for stroke prevention Aspirin meta analysis 10-20% RRR P=NS AVERROES anticoagulant superior to aspirin 2 1ry outcome 1.6% vs. 3.7% equates to RRR 57% ACTIVE W stopped early 30% RRR with similar bleeding 3 1ry outcome 3.9% vs 5.6% 1 NEJM (1999); 339: NEJM (2011); 364: Lancet (2006); 367:

8 Why consider triple therapy Other considerations: CHA 2 DS 2 VAS 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%

9 Why consider triple therapy Other considerations: CHA 2 DS 2 VAS 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

10 What we know of triple therapy Very little RCT studies undertaken! Cohort data VKA and DAPT Guidance NICE ESC NOACs and DAPT

11 Crude incidence rates of fatal and nonfatal bleeding according to antithrombotic regimen in time periods following inclusion. Lamberts M et al. Circulation. 2012;126: Copyright American Heart Association, Inc. All rights reserved.

12 ESC survey 2014 Europace (2014) 16,

13 ESC survey 2014 Europace (2014) 16,

14 WOEST Lancet (2013); 381: 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

15 WOEST: Primary End point: Total number of bleeding events (TIMI criteria) Lancet (2013); 381:

16 WOEST: Secondary End points: Break down of bleeding events (TIMI criteria) Lancet (2013); 381:

17 WOEST: Secondary End points: MACE inc. death, MI, TVR, Stroke, ST Lancet (2013); 381:

18 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

19 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

20 ESC 2010 AF recommendations European Heart Journal (2010) 31,

21 Data with NOACs?

22 APPRAISE-2 N Engl J Med 2011;365: Apixaban 5mg bd when added following ACS and DAPT Stopped early due to increase major bleed with no counterbalance in reduction of ischaemic events

23 RE-DEEM European Heart Journal doi: /eurheartj/ehr113 Dabigatan vs. placebo in patients th ACS on DAPT phase II study Dose ranging from 50, 75, 110 and 150mg bd

24 ATLAS ACS 2-TIMI 51 NEJM (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

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

26 ATLAS ACS 2-TIMI 51 NEJM (1):9-19 NNT 63 NNT 53 NNT 72 NNT - NA

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

28 Future trials with NOACs

29 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

30 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

31 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

32 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

33 Case 1 Stroke vs IST CHA 2 DS 2 VASc = 2 2.2% per yr 0.18% per month STEMI trust policy ticagrelor Bleeding HAASBLED = 0

34 Case 1 Stroke vs IST CHA 2 DS 2 VASc = 2 2.2% per yr 0.18% per month STEMI trust policy ticagrelor Bleeding HAASBLED = 0 OPTIONS: DURATION? Aspirin Clopidogrel Warfarin Ticagrelor Prasugrel 1, 3, 6, 12 months? NOAC (or none!)

35 Case 1 Stroke vs IST CHA 2 DS 2 VASc = 2 2.2% per yr 0.18% per month STEMI trust policy ticagrelor Bleeding HAASBLED = 0 OPTIONS: DURATION? Aspirin Clopidogrel Warfarin Ticagrelor Prasugrel 1, 3, 6, 12 months? NOAC (what dose?) (or none!)

36 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

37 Case 2 Stroke vs IST CHA 2 DS 2 VASc =6 9.8% per yr 0.82% per month NSTEMI risk assess CRUSADE / GRACE Bleeding HAASBLED = 4

38 Case 2 Stroke vs IST CHA 2 DS 2 VASc =6 9.8% per yr 0.82% per month NSTEMI risk assess CRUSADE / GRACE Bleeding HAASBLED = 4 OPTIONS: DURATION? Aspirin Clopidogrel Warfarin Ticagrelor Prasugrel 1, 3, 6, 12 months? NOAC (or none!)

39 Case 2 Stroke vs IST CHA 2 DS 2 VASc =6 9.8% per yr 0.82% per month NSTEMI risk assess CRUSADE / GRACE Bleeding HAASBLED = 4 OPTIONS: DURATION? Aspirin Clopidogrel Warfarin Ticagrelor Prasugrel 1, 3, 6, 12 months? NOAC (or none!)

40 Questions