La gestion du traitement par NOAC chez le patient avec une cardiopathie ischémique. Par le Pr C. Hermans

1. LA GESTION DU TRAITEMENT
PAR NOAC
CHEZ LE PATIENT
AVEC UNE CARDIOPATHIE
ISCHÉMIQUE
Professeur Cedric HERMANS, MD, PhD, MRCP (Lon), FRCP (Lon, Edin)
Haemostasis and Thrombosis Unit
Haemophilia Clinic
Division of Haematology
Cliniques Universitaires Saint-Luc
Catholic University of Louvain
1200 Brussels, Belgium
Cedric.hermans@uclouvain.be Bruxelles Novembre 2014

2. OLD VERSUS NEW ANTICOAGULANTS :
MULTIPLE- VERSUS SINGLE-FACTOR INHIBITION
VKAs LMWHs Anti-Xa
Anti-IIa
Mode of action Interference with Vit K
recycling
Potentiation of
antithrombin
Direct inhibition
Targets FII, FVII, FIX, FX
Reduced synthesis
Indirect inhibition of
FXa and FIIa
Selective inhibition
of FXa or FIIa
Efficacy Universal anticoagulants
including Mechanical Cardiac
Valve
Universal anticoagulants
Acute phase of PE
Prevention and treatment
of VTE
Prevention of stroke in AF
…

3. LES NOUVEAUX ANTICOAGULANTS ORAUX (DIRECTS)
INHIBITION DIRECTE ET CIBLÉE DU FXA OU DU FIIA (THROMBINE)
Fibrinogène Fibrine
IIa
Prothrombine
Xa + Va
X
Tissue Factor-VIIa
IXaIX
VIIIaRivaroxaban (Xarelto) (Bayer)
Apixaban (Eliquis) (BMS / PFIZER)
Edoxaban (Lixiana) (Daiichi Sankyo)
Dabigatran Etexilate (Pradaxa)
(Boehringer-Ingelheim)
Pradaxa / Dabigatran : anti-thrombine
E Liqui S : E pour equilibrium - Liqui pour liquid and S pour Stability
Xarelto : Xa, RELiable, Treatment, Oral Cedric HERMANS UCL 2014

4. COMPARAISON DES NOUVEAUX ANTICOAGULANTS ORAUX
Apixaban
ELIQUIS
Rivaroxaban
XARELTO
Dabigatran
PRADAXA
Mécanisme d’action Inhibition directe FXa Inhibition directe FXa Inhibition directe FIIa
Biodisponibilité orale ~50 % 80 % 6.5 %
Voie d’administration orale orale orale
Posologie 2x/jour
1x/jour (FA, MTEV)
1x/jour (prévention
MTEV)
2x/jour (MTEV, FA)
Pro-drogue Non Non Oui
Interférence alimentaire Non Non Non
Elimination rénale ~27 % 36 % 85 %
Demi-vie (T1/2) ~12h 7–11 h 14–17 h
Tmax 3 h 2–4 h 0.5–2 h
Interférences
médicamenteuses
Inhibiteurs CYP 3A4 et
P-gp
Inducteurs CYP 3A4
Inhibiteurs CYP 3A4 et
P-gp
Inducteurs CYP 3A4
Inhibiteurs P-gp
Inducteurs P-gp

5. PROPRIÉTÉS DES NOUVEAUX
ANTICOAGULANTS ORAUX (NACOS)
• Administration orale
• Rapidité de l’effet anticoagulant
• Inhibition directe et ciblée des facteurs Xa ou IIa
• Demi-vie courte (12h)
• Effet prévisible
• Pas d’interférence alimentaire et peu
d’interférences médicamenteuses
• Plus facile à manipuler
• Elimination rénale

6. DEVELOPMENT AND VALIDATION OF NOACS
DVT/VTE
Prophylaxis
Orthopaedic
Surgery
DVT/VTE
Treatment
AF/Stroke
Prevention
DVT/VTE
Prophylaxis
Medical
patients
Acute coronary
syndrome
Cedric HERMANS UCL 2014

7. NOACS AND ATRIAL FIBRILLATION
09/2009
09/2011
09/2011
Cedric HERMANS 2014

8. EFFICACITÉ DES NOACS PAR RAPPORT AUX AVKS
CHEZ LES PATIENTS EN FA
Pradaxa
110 mgx2
Pradaxa
150 mgx2
Xarelto
20 mg
Apixaban
5 (2.5) mgx2
Prévention AVC +
embole systémique
Pradaxa = AVK Pradaxa meilleur Xarelto = AVK *
> AVK **
Apixaban meilleur
Prévention AVC
ischémique
Pradaxa = AVK Pradaxa meilleur Xarelto = AVK Apixaban = AVK
AVC hémorragique Pradaxa meilleur Pradaxa meilleur Xarelto meilleur Apixaban meilleur
Hémorragie
majeure
Pradaxa meilleur Pradaxa = AVK Xarelto = AVK Apixaban meilleur
Hémorragie
digestive majeure
Pradaxa = AVK Pradaxa moins
bon
Xarelto moins
bon
Apixaban = AVK
Hémorragie
cérébrale
Pradaxa meilleur Pradaxa meilleur Xarelto meilleur Apixaban =
meilleur
* Analyse ITT ** Analyse On-Treatment

9. Age: 73
Presentation:
• ACS diagnosed in ED
• Underlying paroxysmal NVAF
identified
• Transferred to cardiac
catheterization lab for diagnostic
coronary angiography & PCI with
DES
Additional information:
• CHA2DS2-VASc = 3
• HAS-BLED = 2
Current medications:
• ASA
Maria has arrived at the emergency
department with severe chest pain

10. Atrial fibrillation
and coronary artery disease
• New onset AF in a patient with a
history of coronary heart disease
– Recent ACS (< 1 year)
– Remote ACS (> 1 year)
• ACS in an AF patient (on NOAC)

11. CARDIOVASCULAR BENEFITS OF NOACS IN
PATIENTS WITH AF AND CONCOMITANT USE OF
ANTIPLATELET AGENT(S)

12. 1. Dans AL et al. Circulation 2013;127:634–40; 2. Patel MR et al. N Engl J Med 2011;365:883–91;
3. Goodman SG et al. J Am Coll Cardiol 2014;63:891–900; 4. Granger CB et al. N Engl J Med 2011;365:981–92
Concomitant use antiplatelet agents in patients with AF
treated with NOACs
ROCKET-AF (rivaroxaban)
• 36% of patients received concomitant ASA; clopidogrel contraindicated2
• Prior ASA independently associated with increased risk of major bleeding3
RE-LY® (dabigatran)
• 38.4% of patients received antiplatelets, including ASA alone (32.0%), clopidogrel
alone (1.9%), or both (4.5%)
• Benefits of dabigatran vs warfarin consistent irrespective of concomitant antiplatelets1
ARISTOTLE (apixaban)
• 31% of patients received concomitant ASA; clopidogrel contraindicated4
• Benefits of apixaban vs warfarin consistent irrespective of concomitant ASA4

13. NOACS + ANTI-PLAQUETTAIRES
RISQUE HÉMORRAGIQUE
06 March 2015 13
Circulation. 2013 Feb 5;127(5):634-40.

14. NOAC + Antiplatelets
06 March 2015 14
Circulation. 2013 Feb 5;127(5):634-40.

16. Dans AL et al. Circulation 2013;127:634–40
Benefits of dabigatran at both dosages vs warfarin
consistent irrespective of concomitant antiplatelet use
No antiplatelet Antiplatelet Antiplatelet
1.251.000.50 1.75
Dabigatran 110 mg BID
vs warfarin
0.25
Favours dabigatran Favours warfarin Favours dabigatran Favours warfarin
0.75 1.501.251.000.50 1.750.25 0.75 1.50
Stroke/SE
All stroke
Ischaemic stroke
CV death
Major bleed
Minor bleed
All bleed
Intracranial
Extracranial
P(inter)
0.74
0.72
0.67
0.67
0.79
0.51
0.85
0.37
0.84
P(inter)
0.06
0.04
0.08
0.36
0.87
0.39
0.50
0.53
0.64
Dabigatran 150 mg BID
vs warfarin

18. APIXABAN VS WARFARIN WITH CONCOMITANT AAS
John H. Alexander at al, European Heart Journal 2013

19. MYOCARDIAL INFARCTION
NO INCREASED RISK OF MI WITH DABIGATRAN
06 March 2015 19

20. Feb 2014
RE-LY® myocardial ischaemic events
subanalysis (2012): cardiac outcomes (1)
Numerical imbalance in rate of MI: not statistically significant for
either dose of dabigatran compared with warfarin
– No imbalance for silent MI or fatal MI
HR = hazard ratio
Hohnloser SH et al. Circulation 2012;125:669–76
20
Event rate (%/yr) D110 vs warfarin D150 vs warfarin
D110 D150 W HR (95% CI) P value HR (95% CI) P value
Total MI 0.82 0.81 0.64 1.29 (0.96–1.75) 0.09 1.27 (0.94–1.71) 0.12
Clinical MI 0.73 0.74 0.56 1.30 (0.95–1.80) 0.10 1.32 (0.96–1.81) 0.09
Silent MI 0.09 0.07 0.08 1.22 (0.50–2.93) 0.66 0.87 (0.34–2.27) 0.72
Fatal MI 0.13 0.11 0.10 1.32 (0.63–2.80) 0.46 1.06 (0.49–2.33) 0.88
AF – warfarin comparator

21. 2013 RELY-ABLE®: Long-term Benefits
Long Term Multi-Center Extension
of Dabigatran Treatment in
Patients with Atrial Fibrillation
Patients taking dabigatran etexilate
were followed for up to a further
4.3yrs after completion of the
RE-LY® trial
Patients continued to receive the
same blinded dose of dabigatran
etexilate as in the RE-LY® trial
1. Connolly SJ. et al. Circulation .2013;128:237–43.
DOSES BLINDED

22. RE-LY® & RELY-ABLE® : Benefits maintained long-term
In the combined RE-LY®/RELY-ABLE® analysis, there were :
• Lower rates of ischaemic and haemorrhagic stroke/SE on dabigatran 150 mg twice
daily versus 110mg twice daily
• Low rates of hemorrhagic stroke on both dosages
• Rates of major bleeding consistent to data from RE-LY®
• Very low rates of intracranial bleeding
• No new safety signals
Data from the RELY-ABLE® analysis is consistent with the findings from RE-LY®
The combined data validate that both doses of dabigatran etexilate are clinically
effective for long-term stroke prevention for patients with non-valvular AF, with a
favourable safety profile sustained during up to 6.7 years of ongoing treatment
1. Connolly SJ. et al. Circulation .2013;128:237–43.

23. Benefit–risk profile of dabigatran confirmed in FDA study of >134 000
Medicare patients
Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg together without stratification by dose. Warfarin is the reference group. CI = confidence interval;
HR = hazard ratio; MI = myocardial infarction; Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)
Incidence rate per 1000 person-years
Adjusted HR
(95% CI)
Dabigatran Warfarin
Ischaemic stroke 11.3 13.9 0.80 (0.67-0.96)
Intracranial haemorrhage 3.3 9.6 0.34 (0.26-0.46)
Major gastrointestinal
bleeding
34.2 26.5 1.28 (1.14-1.44)
Acute myocardial infarction 15.7 16.9 0.92 (0.78-1.08)
Mortality 32.6 37.8 0.86 (0.77-0.96)
Dabigatran was associated with a lower risk of ischaemic stroke,
intracranial haemorrhage and death than warfarin.
Risk of MI was similar for dabigatran and warfarin.
2014

24. RE-LY®2–4 >18 000 patients
0.41
1. www.fda.gov/Drugs/DrugSafety/ucm396470.htm.
2. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 3. Connolly SJ et al. N Engl J Med. 2010;363:1875–6; 4. Pradaxa®: EU SPC 2014
Favourable benefit-risk profile of dabigatran confirmed
in independent FDA study of >134 000 patients
Medicare1 >134 000 patients
0.86 1.28
0.92
0.80
0.34
0.88
1.48
1.27
0.75
In the USA, the licensed doses for dabigatran etexilate are 150 mg BID and 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF
Numbers on bars denote hazard ratios vs warfarin
110 mg BID, indicated for certain patients,
was shown to be as effective as warfarin in preventing stroke or systemic embolism in RE-LY®, which was a
PROBE (prospective, randomized, open-label with blinded endpoint evaluation) trial

25. CABG, coronary artery bypass graft; UA, unstable angina
Hohnloser SH et al. Circulation 2012;125:669–76
Benefits of dabigatran vs warfarin consistent in patients
with or without prior MI or CAD
1.51.00.5 1.51.00.52.0 2.0
P(inter)
0.28
0.72
0.49
0.85
0.66
0.45
0.95
0.91
0.35
0.61
P(inter)
Dabigatran 110 mg BID
vs warfarin
Dabigatran 150 mg BID
vs warfarin
Stroke/SE
MI
MI, UA, PCI,
CABG, CV arrest,
cardiac death
Major bleeding
Net clinical benefit
No prior CAD/MI Prior CAD/MI Prior CAD/MI
0.0 0.0
Favours dabigatran Favours warfarin Favours dabigatran Favours warfarin

26. For medical non-promotional reactive use only
APIXABAN IN PATIENTS WITH
ATRIAL FIBRILLATION AND
PRIOR CORONARY ARTERY
DISEASE
Insights from the ARISTOTLE Trial
Bahit et al. Circulation 2012;126:A13026

27. 27For medical non-promotional reactive use only
Results of the subpopulation with prior CAD
 Of the total study patient population, 36.5% of patients
(n=6639) had prior CAD
 Patients with prior CAD were more often male and had
prior stroke, diabetes mellitus and hypertension compared
with patients without prior CAD
 Patients with prior CAD were more likely to be on aspirin
at baseline (42.2% vs 24.5%; p<0.001) when compared
with patients without prior CAD
Bahit et al. Circulation 2012;126:A13026 CAD, coronary artery disease.

28. 28For medical non-promotional reactive use only
Adapted from Bahit et al. Circulation 2012;126:A13026
Prior CAD
All-cause death
4.21 4.40 0.96 (0.81–1.13)
No prior CAD 3.11 3.68 0.85 (0.73–0.98)
Prior CAD
Intracranial bleeding
0.27 0.73 0.36 (0.20–0.66)
No prior CAD 0.37 0.85 0.44 (0.30–0.65)
Prior CAD
ISTH major bleeding
2.39 3.05 0.78 (0.62–0.98)
No prior CAD 1.99 3.12 0.64 (0.53–0.76)
Prior CAD
Myocardial infarction
0.95 1.00 0.95 (0.66–1.35)
No prior CAD 0.29 0.39 0.75 (0.47–1.20)
Prior CAD
Stroke or SE
1.47 1.55 0.95 (0.71–1.27)
No prior CAD 1.15 1.63 0.70 (0.56–0.89)
Rate (%/yr) HR 95% CI
p value for
interaction
0.2786
0.5867
0.1724
0.4491
0.1148
0.2 0.5 1 2
Favours apixaban Favours warfarin
Results
Apixaban Warfarin
CAD, coronary artery disease; CI, confidence interval;
HR, hazard ratio; SE, systemic embolism.

29. 29For medical non-promotional reactive use only
Conclusions
 In patients with atrial fibrillation, apixaban reduces stroke
or systemic embolism and causes less bleeding and
death compared with warfarin
 These treatment effects were consistent in patients with
and without a history of coronary artery disease
Bahit et al. Circulation 2012;126:A13026

30. NOAC AND ACUTE
CORONARY SYNDROME

31. Lip GY et al. Thromb Haemost 2010;103:13–28
AF + ACS requires treatment with both anticoagulant and
antiplatelet therapy
31
~30% of patients with AF and an indication for continuous OAC have
co-existing CAD and may require PCI
An estimated 1–2 million anticoagulated patients in Europe are
candidates for PCI procedures
Long-term anticoagulant
therapy is essential for
prevention of recurrent
ischaemic events
Initial antiplatelet
therapy is essential for
prevention of stent
thrombosis following PCI

36. 573 patients receiving OAC and undergoing PCI in open-label, randomized WOEST trial
TVR, target vessel revascularisation; ST, stent thrombosis; TIMI, thrombolysis in myocardial infarction bleeding criteria
Dewilde WJ et al. Lancet 2013;381:1107–15
WOEST: exclusion of ASA from combination therapy is
associated with improved outcomes vs triple therapy
OAC + clopidogrel associated with significant reduction in major bleeding and no
increase in thrombotic events vs triple therapy with OAC + clopidogrel + ASA
Total number of TIMI bleeding events Death, MI, TVR, stroke, ST
Time (days)
100
80
60
40
30
0
30 60 120 180 270 365
Cumulativeincidence(%)
19.4%
44.4%
HR: 0.36 (95% CI: 0.26‒0.50) P<0.0001
17.6%
11.1%
HR: 0.60 (95% CI: 0.38‒0.94) P=0.025
90
70
50
10
20
0 90
Triple-therapy group
Double-therapy group
100
80
60
40
30
0
30 60 120 180 270 365
90
70
50
10
20
0 90
Time (days)
Triple-therapy group
Double-therapy group
210
253
194
244
181
241
173
236
159
226
140
208
284
279
186
241
272
276
270
273
261
266
252
263
242
258
223
234
284
279
266
270
Triple therapy
Double therapy
Number at risk
Cumulativeincidence(%)

37. Syndrome coronarien aigu et NOACs
• PRADAXA
– Etude Re-Deem
• APIXABAN
– Etude « Appraise-2 »
interrompue pour excès
de saignements
• XARELTO
– ATLAS ACS 2-TIMI 51 trial

38. XARELTO AND ACS
Indication Dose and
regimen
Duration of therapy Patient
population
Prevention of
atherothrombotic
events in patients
with elevated cardiac
biomarkers after
an ACS in
combination
with antiplatelet
therapy
2.5 mg bid
co-administered
with ASA alone or
with ASA plus
clopidogrel
or ticlopidine
Extension of treatment
>12 months should be
done on an individual
patient basis (limited
experience up to
24 months)
Patients after an
ACS with elevated
cardiac biomarkers
*Moderate renal impairment = CrCl: 30–49 ml/min; severe renal impairment = CrCl: 15–29 ml/min
Bayer Pharma AG. Xarelto® (rivaroxaban) Summary of Product Characteristics. 2013. Available at: http://www.xarelto.com/en/information-on-xarelto/summary-of-product-
characteristics/ [accessed 24 January 2014].

39. Feb 2014
EXPERIENCE WITH DABIGATRAN IN ACS :
RE-DEEM™
• Dose-escalation Phase II trial in patients with recent ACS
 Randomized to placebo or dabigatran (50 mg, 75 mg, 110 mg or 150 mg, all
BID)
 At baseline, >99% of patients were also receiving dual antiplatelet therapy
• Overall, a low number of patients experienced cardiac events
 Minor differences between treatment groups
 In the composite outcome, there were fewer events at higher vs lower doses of
dabigatran
ACS = acute coronary syndromes; BID = twice daily; CV = cardiovascular; D110 = dabigatran 110 mg twice daily;
D150 = dabigatran 150 mg twice daily
Oldgren J et al. Eur Heart J 2011;32:2781–9 39
Placebo Dabigatran
Outcome, n (%)
(n=371)
50 mg BID
(n=369)
75 mg BID
(n=368)
110 mg BID
(n=406)
150 mg BID
(n=347)
CV death, non-fatal MI,
or non-haemorrhagic stroke
14 (3.8) 17 (4.6) 18 (4.9) 12 (3.0) 12 (3.5)
CV death 9 (2.4) 8 (2.2) 9 (2.4) 5 (1.2) 4 (1.2)
Non-fatal MI 4 (1.1) 9 (2.4) 8 (2.2) 7 (1.7) 8 (2.3)
Non-haemorrhagic stroke 3 (0.8) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0)
Severe recurrent ischaemia 9 (2.4) 9 (2.4) 11 (3.0) 9 (2.2) 11 (3.2)
All-cause death 14 (3.8) 8 (2.2) 10 (2.7) 7 (1.7) 7 (2.0)
ACS – placebo comparator

40. Feb 2014
EXPERIENCE WITH DABIGATRAN IN ACS :
RE-DEEM™
• Dose-escalation Phase II trial in patients with recent ACS
 Randomized to placebo or dabigatran (50 mg, 75 mg, 110 mg or 150 mg, all
BID)
 At baseline, >99% of patients were also receiving dual antiplatelet therapy
• Overall, a low number of patients experienced cardiac events
 Minor differences between treatment groups
 In the composite outcome, there were fewer events at higher vs lower doses of
dabigatran
ACS = acute coronary syndromes; BID = twice daily; CV = cardiovascular; D110 = dabigatran 110 mg twice daily;
D150 = dabigatran 150 mg twice daily
Oldgren J et al. Eur Heart J 2011;32:2781–9 40
Placebo Dabigatran
Outcome, n (%)
(n=371)
50 mg BID
(n=369)
75 mg BID
(n=368)
110 mg BID
(n=406)
150 mg BID
(n=347)
CV death, non-fatal MI,
or non-haemorrhagic stroke
14 (3.8) 17 (4.6) 18 (4.9) 12 (3.0) 12 (3.5)
CV death 9 (2.4) 8 (2.2) 9 (2.4) 5 (1.2) 4 (1.2)
Non-fatal MI 4 (1.1) 9 (2.4) 8 (2.2) 7 (1.7) 8 (2.3)
Non-haemorrhagic stroke 3 (0.8) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0)
Severe recurrent ischaemia 9 (2.4) 9 (2.4) 11 (3.0) 9 (2.2) 11 (3.2)
All-cause death 14 (3.8) 8 (2.2) 10 (2.7) 7 (1.7) 7 (2.0)
ACS – placebo comparator
In this high-risk patient population, no negative effect of dabigatran on
myocardial ischaemic events was reported

41. Feb 2014
EXPERIENCE WITH DABIGATRAN IN ACS :
RE-DEEM™
• Dose-escalation Phase II trial in patients with recent ACS
 Randomized to placebo or dabigatran (50 mg, 75 mg, 110 mg or 150 mg, all
BID)
 At baseline, >99% of patients were also receiving dual antiplatelet therapy
• Overall, a low number of patients experienced cardiac events
 Minor differences between treatment groups
 In the composite outcome, there were fewer events at higher vs lower doses of
dabigatran
ACS = acute coronary syndromes; BID = twice daily; CV = cardiovascular; D110 = dabigatran 110 mg twice daily;
D150 = dabigatran 150 mg twice daily
Oldgren J et al. Eur Heart J 2011;32:2781–9 41
Placebo Dabigatran
Outcome, n (%)
(n=371)
50 mg BID
(n=369)
75 mg BID
(n=368)
110 mg BID
(n=406)
150 mg BID
(n=347)
CV death, non-fatal MI,
or non-haemorrhagic stroke
14 (3.8) 17 (4.6) 18 (4.9) 12 (3.0) 12 (3.5)
CV death 9 (2.4) 8 (2.2) 9 (2.4) 5 (1.2) 4 (1.2)
Non-fatal MI 4 (1.1) 9 (2.4) 8 (2.2) 7 (1.7) 8 (2.3)
Non-haemorrhagic stroke 3 (0.8) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0)
Severe recurrent ischaemia 9 (2.4) 9 (2.4) 11 (3.0) 9 (2.2) 11 (3.2)
All-cause death 14 (3.8) 8 (2.2) 10 (2.7) 7 (1.7) 7 (2.0)
ACS – placebo comparator
Although it was not the primary endpoint or objective of the study, there was a
trend towards fewer events with D110 and D150 than with placebo

42. Feb 2014
EXPERIENCE WITH DABIGATRAN IN ORTHOPAEDIC SURGERY
• ACS events were centrally adjudicated in three Phase III trials of
VTE prevention in orthopaedic surgery
 RE-MODEL™, RE-NOVATE®, RE-MOBILIZE® (total >8000 patients)
• Rates of ACS (definite/likely) events were low and similar for
patients treated with dabigatran (150 mg or 220 mg OD combined)
and enoxaparin
OD = once daily
Eriksson BI et al. Thromb Res 2012;130:396–402; Clemens A et al. Vasc Health Risk Manag 2013;9:599–615 42
Adjudicated ACS events, n (%)
Dabigatran
(n=5419)
Enoxaparin
(n=2716)
Definite/likely 42 (0.8) 20 (0.7)
Definite 28 (0.5) 17 (0.6)
Primary VTE prevention – enoxaparin comparator

43. Feb 2014
EXPERIENCE WITH DABIGATRAN IN ORTHOPAEDIC SURGERY
• ACS events were centrally adjudicated in three Phase III trials of
VTE prevention in orthopaedic surgery
 RE-MODEL™, RE-NOVATE®, RE-MOBILIZE® (total >8000 patients)
• Rates of ACS (definite/likely) events were low and similar for
patients treated with dabigatran (150 mg or 220 mg OD combined)
and enoxaparin
OD = once daily
Eriksson BI et al. Thromb Res 2012;130:396–402; Clemens A et al. Vasc Health Risk Manag 2013;9:599–615
43
Adjudicated ACS events, n (%)
Dabigatran
(n=5419)
Enoxaparin
(n=2716)
Definite/likely 42 (0.8) 20 (0.7)
Definite 28 (0.5) 17 (0.6)
Primary VTE prevention – enoxaparin comparator
No negative effect of dabigatran on myocardial ischaemic events was
reported

44. APIXABAN
1. The APPRAISE-2 study was a Phase III clinical trial in patients
with recent acute coronary syndrome treated with apixaban 5 mg
twice daily or placebo in addition to mono or dual antiplatelet
therapy.
2. This study was stopped early due to an increase in bleeding which
was not offset by clinically meaningful reductions in ischaemic
events.1
Alexander JH, et al; APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute
coronary syndrome. N Engl J Med 2011;365:699-708.

45. AF (NOAC) + ACS/PCI

46. Aug 2014
ESC Working Group consensus
Antithrombotic treatment following coronary artery stenting in AF
patients at moderate to high risk of TE (in whom OAC is required)
46
New antiplatelets such as prasugrel and ticagrelor have not yet been evaluated with OACs
BMS = bare metal stent; DES = drug-eluting stent; ESC = European Society of Cardiology;
RCT = randomized controlled trial; TE = thromboembolism
1. Lip GYH et al. Thromb Haemost 2010;103:13–28; 2. Heidbuchel H et al. Europace 2013;15:625–51
Short-term
• Triple therapy: warfarin + ASA + clopidogrel
• Duration varies from 2–4 weeks (high haemorrhagic risk, elective
PCI and BMS) to 6 months (low/intermediate haemorrhagic risk,
ACS, BMS/DES)
• Followed by warfarin + either clopidogrel or ASA for up to 12 months in
some patient groups (ACS or DES)
Lifelong
• Warfarin alone

47. Aug 2014
ESC Working Group consensus
Antithrombotic treatment following coronary artery stenting in AF
patients at moderate to high risk of TE (in whom OAC is required)
47
New antiplatelets such as prasugrel and ticagrelor have not yet been evaluated with OACs4
BMS = bare metal stent; DES = drug-eluting stent; ESC = European Society of Cardiology;
RCT = randomized controlled trial; TE = thromboembolism
1. Lip GYH et al. Thromb Haemost 2010;103:13-28; 2. Heidbuchel H et al. Europace 2013;15:625–51
Short-term
• Triple therapy: warfarin + ASA + clopidogrel
• Duration varies from 2–4 weeks (high haemorrhagic risk, elective
PCI and BMS) to 6 months (low/intermediate haemorrhagic risk,
ACS, BMS/DES)
• Followed by warfarin + either clopidogrel or ASA for up to 12 months in
some patient groups (ACS or DES)
Lifelong
• Warfarin alone
These recommendations are based on OAC being indicated for patients with AF
and stroke risk factors, and dual antiplatelet therapy being indicated after
ACS or PCI

49. Lip GYH et al. Eur Heart J. 2014;doi:10.1093/eurheartj/ehu298
Latest guidance for combination therapy in patients with
NVAF and ACS/PCI
In general, the period of triple therapy should be as short as
possible, followed by OAC plus a single antiplatelet therapy
(preferably clopidogrel 75 mg/d, or as an alternative, ASA
75–100 mg/d)
B
Level
I
Class
Long-term antithrombotic therapy with OAC (beyond 12
months) is recommended in all patients
Recommendation
CIIb
Where a NOAC is used in combination with clopidogrel and/or
low-dose ASA, the lower tested dose for stroke prevention in
AF (dabigatran 110 mg BID, rivaroxaban 15 mg OD, or
apixaban 2.5 mg BID) may be considered
General
recommendation

50. *Dual therapy with oral anticoagulation and clopidogrel may be considered in selected patients; **ASA as an alternative to
clopidogrel may be considered in patients on dual therapy (i.e. oral anticoagulation plus single antiplatelet); ***Dual therapy
with oral anticoagulation and an antiplatelet agent (ASA or clopidogrel) may be considered in patients at very high risk of
coronary events. DAPT, dual antiplatelet therapy; Lip et al Eur Heart J 2014 doi:10.1093/eurheartj/ehu298
Latest guidance for combination therapy in patients with
NVAF and ACS/PCI (2)
STEP 1 – Stroke risk
STEP 2 – Bleeding risk
STEP 3 – Clinical setting
STEP 4 –
Antithrombotic
therapy
Nonvalvular atrial fibrillation
CHA2DS2-VASc = 1 CHA2DS2-VASc ≥ 2
Low to intermediate
(e.g. HAS-BLED = 0–2)
High
(e.g. HAS-BLED ≥ 3)
Low to intermediate
(e.g. HAS-BLED = 0–2)
High
(e.g. HAS-BLED ≥ 3)
Stable CAD ACS Stable CAD ACS Stable CAD ACS Stable CAD ACS
Triple
or dual
therapy*
or DAPT
Triple
therapyO A C
A C
O A C
Dual
therapy
or DAPT
O C
Triple
or dual
therapy*
O A C
Triple
or dual
therapy*
O A C
Triple
therapy
O A C
O A COral anticoagulation ASA 75–100 mg daily Clopidogrel 75 mg daily
If PCI is
performed
If PCI is
performed
If PCI is
performed
If PCI is
performed
Time from PCI/ACS
Lifelong
12 months
6 months
4 weeks
0
Dual
therapy**
Dual
therapy**
or DAPT
O A or C
A C
O A or C
A C
Dual
therapy**
O A or C
Triple or
dual
therapy*
O A C
Triple
or dual
therapy*
O A C
Triple
or dual
therapy*
O A C
Dual
therapy**
Dual
therapy**
O A or C O A or C
Monotherapy***O
Dual
therapy**
O A or C
Monotherapy***O

53. Not head-to-head comparison; no clinical conclusions can be drawn
A2.5 = apixaban 2.5 mg BID; D110 = dabigatran etexilate 110 mg BID; R15 = rivaroxaban 15 mg OD
Lip GYH et al. Eur Heart J. 2014;doi:10.1093/eurheartj/ehu298
Use of low dose NOAC in recent AF trials
50% of
dabigatran group
received D110
n=6015
21% of
rivaroxaban group
received R15
n=1474
4.7% of
apixaban group
received A2.5
n=428
Tested among all eligible
patients in RE-LY®
May be considered on its
own merits
Prescribed only to a minority subset of patients in
clinical trials
May not necessarily provide adequate
antithrombotic protection for AF in patients without
the clinical features used for dose adjustment

54. TRIPLE THERAPY WITH A NOAC :
KEY MESSAGES
54
• Oral anticoagulation with VKA OR NOAC
• No preference within class of NOACs
• Use lower tested dose
• Dabigatran 110 mg is the only
lower dose with proven efficacy in
randomised patients
• Other measures to limit
bleeding risk during thriple
therapy:
• 1. Use of clopidogrel (Plavix)
instead of ticagrelor (Brilique),
prasugrel (Efient)
• 2. Low dose aspirin <100 mg OD
• 3. Radial access
• 4. Consider intiating PPI

55. ONGOING TRIALS IN PATIENTS WITH AF
UNDERGOING A PCI WITH STENTING
55
Studies Interventions
PIONEER AF-PCI Safety of two rivaroxaban regimens vs VKA
RE-DUAL PCI Efficacy and safety of dual therapy with
dabigatran vs. triple therapy with VKA
www.clinicaltrials.gov

56. 1160.186 - RE-DUAL PCI
A prospective Randomised, open label, blinded endpoint
(PROBE) study to Evaluate DUAL antithrombotic therapy with
dabigatran etexilate (110mg and 150mg b.i.d.) plus clopidogrel
or ticagrelor vs. triple therapy strategy with warfarin (INR 2.0 –
3.0) plus clopidogrel or ticagrelor and aspirin in patients with
non valvular Atrial Fibrillation (NVAF) that have undergone a
percutaneous coronary intervention (PCI) with stenting.

57. *Warfarin arm: 1 month after bare metal stent or 3 months after drug-eluting stent
Adapted from Cannon C. AHA 2013; and Boehringer Ingelheim data on file
RE-DUAL PCI™: two new approaches to improving care
for patients with AF undergoing PCI
Dual primary endpoints: Death, MI, stroke/SE and major bleeding
Patients with AF
undergoing PCI (n=8520)
R
Dabigatran 150 mg BID
+ clopidogrel/ticagrelor
Screening
0–72 hours
after PCI
Dabigatran 110 mg BID
+ clopidogrel/ticagrelor
Warfarin (INR 2.0–3.0)
+ clopidogrel/ticagrelor*
n=2840 patients
per arm
Minimum treatment duration: 6 months

58. PIONEER AF-PCI : OVERVIEW
PCI STUDY
Primary endpoint
 Composite of TIMI major bleeding events, minor bleeding events and bleeding events
requiring medical attention
Key inclusion criteria
 History of paroxysmal, persistent
or permanent non-valvular AF
 Undergone PCI (with stent
placement) for primary
atherosclerotic disease
Key exclusion criteria
 High bleeding risk or contraindication to
anticoagulation
 Prior stroke/TIA
 CrCl <30 ml/min
 Hepatic disease
www.clinicaltrials.gov/ct2/show/NCT01830543 Back to programme overview

59. 59
PIONEER AF-PCI: OVERVIEW
PCI STUDY
Rivaroxaban 15 mg od#‡ + clopidogrel*
Objective: safety of two rivaroxaban regimens vs VKA after PCI (with stent placement)
in non-valvular AF
End of
treatment
(12 months)
Rivaroxaban 2.5 mg bid‡
+ DAPT**
VKA (INR 2.0–3.0)§
+ DAPT*
Rivaroxaban 15 mg od#
+ low-dose ASA
VKA + low-dose
ASA
N=2100
1:1:1 Intended DAPT duration
of 1, 6 or 12 months
Population:
Paroxysmal, persistent
or permanent AF,
undergoing PCI
(with stent placement)
R
* alternative use of prasugrel or ticagrelor allowed, but capped at 15%
** ASA (75–100 mg daily) + clopidogrel (75 mg daily) (alternative use of prasugrel or ticagrelor allowed, but capped at 15%); #CrCl
30–49 ml/min: 10 mg od; ‡First dose 72–96 hours after sheath removal; §First dose 12–72 hours after sheath removal
www.clinicaltrials.gov

60. Conclusions
• Management of NVAF patients with IHD is
complex
• Need for robust data on new antithrombotic
strategies (trials ongoing) (RE-DUAL PCI)
• Recent consensus recommendations are
useful

61. New onset AF / Recent ACS (< 1 year)
Low – moderate atherothrombotic
risk
VKA monotherapy after 1-6 months
NOAC (low-dose) = good alternative to VKA
High atherothrombotic risk VKA + Clopidogrel
NOAC (low-dose) = good alternative to VKA
Low CHA2DS2-VASC score and high
atherothrombotic risk
AAS + Clopidogrel
New onset AF / Remote ACS (> 1 year)
VKA alone is superior to Aspirin post-ACS > no antiplatelet needed for most patients
with AF and stable CAD
Advantages of NOCAs over VKAs are preserved in stable CAD patients with AF,
NOACs provide safe and effective alternatives to VKAs

62. *Dual therapy with oral anticoagulation and clopidogrel may be considered in selected patients; **ASA as an alternative to
clopidogrel may be considered in patients on dual therapy (i.e. oral anticoagulation plus single antiplatelet); ***Dual therapy
with oral anticoagulation and an antiplatelet agent (ASA or clopidogrel) may be considered in patients at very high risk of
coronary events. DAPT, dual antiplatelet therapy; Lip et al Eur Heart J 2014 doi:10.1093/eurheartj/ehu298
Latest guidance for combination therapy in patients with
NVAF and ACS/PCI (2)
STEP 1 – Stroke risk
STEP 2 – Bleeding risk
STEP 3 – Clinical setting
STEP 4 –
Antithrombotic
therapy
Nonvalvular atrial fibrillation
CHA2DS2-VASc = 1 CHA2DS2-VASc ≥ 2
Low to intermediate
(e.g. HAS-BLED = 0–2)
High
(e.g. HAS-BLED ≥ 3)
Low to intermediate
(e.g. HAS-BLED = 0–2)
High
(e.g. HAS-BLED ≥ 3)
Stable CAD ACS Stable CAD ACS Stable CAD ACS Stable CAD ACS
Triple
or dual
therapy*
or DAPT
Triple
therapyO A C
A C
O A C
Dual
therapy
or DAPT
O C
Triple
or dual
therapy*
O A C
Triple
or dual
therapy*
O A C
Triple
therapy
O A C
O A COral anticoagulation ASA 75–100 mg daily Clopidogrel 75 mg daily
If PCI is
performed
If PCI is
performed
If PCI is
performed
If PCI is
performed
Time from PCI/ACS
Lifelong
12 months
6 months
4 weeks
0
Dual
therapy**
Dual
therapy**
or DAPT
O A or C
A C
O A or C
A C
Dual
therapy**
O A or C
Triple or
dual
therapy*
O A C
Triple
or dual
therapy*
O A C
Triple
or dual
therapy*
O A C
Dual
therapy**
Dual
therapy**
O A or C O A or C
Monotherapy***O
Dual
therapy**
O A or C
Monotherapy***O