1. Triple Antithrombotic Therapy in Cardiac Patients
Elizaveta P. Panchenko, MD,PhD
Cardiology Research and Production Center
Moscow
Russian Federation
September 17, 2014

2. Disclosures Consultancy fees or honoraria from SANOFI, Takeda-NYCOMED,
Boehringer Ingelheim,
Pfizer,
Bristol-Myers Squibb,
Bayer,
Lilly,
AstraZeneca,
GlaxoSmithKline,
MEDICINES

3. Triple antithrombotic therapy
Aspirin
Р2Y12 antagonists: clopidogrel, prasugrel, ticagrelor
Oral anticoagulants: vitamin K antagonists, dabigatran, apixaban, rivaroxaban

4. Cardiac Patients Who Need Triple Antithrombotic Therapy
Patients with indications for long anticoagulant therapy: atrial fibrillation, venous thromboembolism, mechanical valve surgery, thrombosis of left ventricle
If they have acute coronary syndrom (ACS)
If they need elective PCI because of angina pectoris
Long –term treatment with oral anticoagulant is necessary in pts with AF, VTE, mechanical heart valves and other clinical situations. Up to 20-30% of pts on VKA have the concomitant diagnosis of CAD and thus are potential candidates for percutaneous coronary intervention (PCI) with stenting. In these cases, double antiplatelet therapy is indicated to prevent stent thrombosis.

5. COEXISTENCE OF CORONARY ARTERY DISEASE AND ATRIAL FIBRILLATION
Analysis of 261 consecutive pts with AF undergoing CAG:
The rate of CAD – 34%
The need of PCI /CABG – 21%
The frequency of AF (Meta-analysis pts from 10 clinical trials)
- in pts with STEMI – 8%
- in pts with NSTE-ACS - 6,4%
% of pts with ACS have AF
1-Kralev et al., PLoSOne.2011;6:e24964.
2-Lopes et al. Heart.2008;94:
3-Schmitt et al., EHJ.2009; 30:

6. BOTH DISEASES DEMAND ANTITHROMBOTIC THERAPY
Acute Coronary Syndrome
Aspirin (forever)
Р2Y12 inhibitor: Clopidogrel, Prasugrel, Ticagrelor (12 months)
Atrial Fibrillation
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Aspirin
Aspirin+Clopidogrel
According to modern recommendations both diseases demand administration of antithrombotic therapy. ACS patients need of two antiplatelet agents: aspirin and one of P2Y12 inhibitors (clopidogrel or prasugrel or ticagrelor). And patients with AF are needed in oral anticoagulant (warfarin, or one of new anticoagulants). Efficacy of aspirin and dual antiplattlet therapy is significant lower than anticoagulants in stroke prevention.
Dual antiplatelet therapy
Anticoagulant

7. Achilles' heel
Bleedings worsen the outcomes in patients receiving the antithrombotic therapy
Now is well established that severe bleeding may have deleterious effects on mortality.

8. BLEEDINGS SIGNIFICANTLY INCREASE THE RISK OF DEATH
The OASIS -5 study was the first demonstrated this position. In this study enoxaparin was compared with fondaparinux in ACS pts. The study demonstrated that there were less bleeding complications in fonda group and bleeding increases risk of death significantly
OASIS-5 dataset

9. What do we know about the frequency of bleedings in patients with antithrombotic therapy?

10. Major Bleedings In AF Patients Receiving Antithrombotic Therapy
Randomized trials
Aspirin
Aspirin + Clopidogrel
Warfarin
1,3%(ACTIVE-A)
1,2%(AVERROES)
2,0% (ACTIVE-W)
1,5-3,0%

11. Antithrombotic therapy
ANTITHROMBOTIC THERAPY AND RISK OF BLEEDINGS IN PATIENTS WITH ATRIAL FIBRILLATION
70,760 patients with AF (UKGPRD registry)
years follow up
10,850 patients had bleedings during follow up
Antithrombotic therapy HR
95% CI
Warfarin
2,08
1,95-2,23
Clopidogrel
1,57
1,37-1,81
Aspirin
1,25
1,17-1,34
Aspirin + Clopidogrel
1,68
1,44-1,97
Warfarin+Aspirin
2,87
2,58-3,19
Warfarin+Clopidogrel
2,74
2,14-3,51
Warfarin+Aspirin+Clopidogrel
3,75
2,7-5,19
As you can see from the results of this register, which reflects the real clinical practice, addition of both aspirin and clopidogrel to the drug regimen of patients already on anticoagulants increases the risk of bleeding.

12. Fatal and nonfatal bleedings
Fatal and nonfatal bleedings* according to antithrombotic regimen in time periods following inclusion (Denmark register)
11480 pts with AF and MI/PCI between y.
Mean age -75,6 y.
Male -60,9%
Triple-22,6%
VKA+ ASP/CLOPI - 20,3%
VKA
Crude incidence rates of fatal and nonfatal bleeding according to antithrombotic regimen in time periods following inclusion. Error bars show standard errors. Triple therapy includes aspirin, clopidogrel, and vitamin K antagonists (VKAs); VKA+single antiplatelet therapy includes VKA+aspirin or clopidogrel; dual antiplatelet therapy includes aspirin and clopidogrel; VKA monotherapy includes only VKA; single antiplatelet therapy includes aspirin or clopidogrel.
*- reguiring hospitalisation
Lamberts M et al. Circulation. 2012;126:

13. HOW TO MINIMIZE THE RISK OF BLEEDINGS?
To decrease the number of antithrombotic drugs

14. What do we know about efficacy and safety of antiplatelet drugs in prevention of stroke in AF patients?

15. STROKE PREVENTION IN ATRIAL FIBRILLATION
ASPIRIN IS superior to PLACEBO

16. STROKE PREVENTION IN AF PATIENTS
ACTIVE-A
ASP+CLOPI are superior to ASP,
but induce more bleedings…
Major bleedings
7,554 pts with AF, those didn’t wish or couldn’t intake warfarin
33 countries, follow-up – 3,6 years % RR
11%
р=0,01
28%
р<0,001
22%
р=0,08 %
2,0%
1,3%
ОР (95%CI)
1,56 ( )
р=0,07
RR (95%CI)
1,57 (1.29-1,92)
р<0,001
0,3%
0,2%
Connolly et all, N Engl J Med 2009;360:

17. STROKE PREVENTION IN ATRIAL FIBRILLATION
Warfarin Is SUPERIOR TO aspirin
VKA therapy is more effective than aspirin, relative risk reduction of stroke/SE on warfarin is 39%
In AF patients with high risk of stroke/SE (>6% per year) RRR is more higher - 50%

18. STROKE PREVENTION IN ATRIAL FIBRILLATION
ACTIVE-W
Warfarin is superior to CLOPI+ASP
Stroke + SE +MI +CVD
Warfarin
Clopi+Asp
Oral anticoagulation is superior to clopidogrel plus ASA in prevention of vascular events. Rates of major hemorrhage are similar.
In warfarin naïve patients curves began to diverge after 6-months lag-period, so warfarin is very effective anticoagulant but with slow beginning of clinical effect
The ACTIVE Writing Group Lancet 2006; 367:

19. VKA Ха
Thrombin
Rivaroxaban
Apixaban
Dabigatran
Edoxaban
The NOACs fall into two classes: the oral direct thrombin inhibitors (dabigatran) and oral direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban)
In contrast to VKAs, which block the formation of multiple active vitamin K dependent coagulation factors (factors II,VII,IX and X), NOACs target selectively the individual step in coagulation cascade
VKA
VKA
VKA
Fibrin

20. STROKE PREVENTION IN ATRIAL FIBRILLATION
Apixaban is Superior to Aspirin
5,599 pts with AF at increased risk of stroke to whom VKA therapy was unsuitable
Randomization Apixaban 5mg twice daily or Aspirin mg per day
Mean follow up period 1,1 year
AVERROES
Stroke or Systemic Embolism
Major Bleeding
Cumulative Hazard

21. All NOACs have demonstrated non-inferiority compare to warfarin with better safety by consistently limiting the number of ICH
Guideline now recommends them as broadly preferable to VKA in the vast majority of patients with NVAF
All NOACs have demonstrated noninferiority compare to warfarin with better safety by consistently limiting the number of ICH
On this basis guideline now

23. What do we know about efficacy and safety of warfarin in patients survived acute coronary syndrome?

24. Aspirin + Warfarin (INR 2,2)
WARFARIN in Patients Survived Acute Coronary Syndrome Conservative strategy of treatment, before «clopidogrel era»
Warfarin (INR 2,0-2,5) in addition to Aspirin 80 mg per day
 the risk of cardio-vascular events (ASPECT-2, OASIS-2, WARIS-II),
 the risk of re-occlusion of IRA in patients with MI and thrombolysis (APRICOT-2)
no increase of major bleeding (ASPECT-2, OASIS-2)
Warfarin (INR 2,8-3,2) is superior to Aspirin 80 mg
 the risk of cardio-vascular events (ASPECT-2, WARIS-II)
Major bleeding
WARIS II
CURE
Aspirin
Aspirin + Warfarin (INR 2,2)
Warfarin (INR 2,8)
Aspirin + Clopidogrel
0,15% per year
0,52% per year
0,58% per year
3,6% per 9 months

25. WARFARIN AND ANTIPLATELET DRUG IN PATIENTS SURVIVED ACUTE CORONARY SYNDROM
WARFARIN +ASPIRIN are better than ASPIRIN in prevention of recurrent events,
moreover, benefits are more than risk of bleeding in patients with medium and low bleeding risk (WARIS-2)
CONSERVATIVE STATEGY

26. HOW TO MINIMIZE THE RISK OF BLEEDINGS?
To decrease the number of antithrombotic drugs
To choose the optimal combination of anticoagulant (VKA or novel oral anticoagulant) and antiplatelet drugs (aspirin or clopidogrel or aspirin+clopidogrel)

27. Is it suitable to withdraw aspirin from triple therapy (asp+clopi+VKA) in patients after PCI?

28. Clopidogrel+VKA versus Clopidogrel+VKA+Aspirin in PCI Patients
An open-labelled, multicentred, randomised, controlled trial
573 on VKA were enrolled, 279 pts assigned double therapy and 284 assigned triple therapy
Indication for oral anticoagulation (AF-67%, Mechanical valve-11%, Other.-20%)
ACS-25-30%; EF-13-15%; Radial access-25-27%
Cumulative incidence of death, MI, Stroke, TVR and stent thrombosis
Incidence of any bleeding
There is only one prospective randomised study WOEST comparing VKA plus clopidogrel with triple therapy in patients undergoing PCI. As you can see from this figure dual therapy was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events. This study was not powered to detect differences in stent thrombosis occurrence.
W JM Dewilde et al., for the WOEST study investigators

29. Death, MI, Stroke, TVR and stent thrombosis (subgroup analysis)
WOEST
Death, MI, Stroke, TVR and stent thrombosis (subgroup analysis) HR
age75
male
t0acs
oacind3cat
des
Overall
FALSE
TRUE no
yes
AF/AFlut
Mechanical valve
Other No
DES
200 79 50
234
195 86
162 25 47 90
194
284 82 65
214
207 69
164 24 48 94
184
279
0.9157
0.8217
0.721
0.1116
0.7761
0.7894
Factor
Age
Gender
ACS
Indication
OAC
Stent
type
Subgroup
<75 years
>75 years
female
Mechanical
valve
BMS
Triple
VKA+Clopi
P-value for interaction
0.7210
double therapy better <=> triple therapy better
0.1
0.4 1
ESC, Hotline III, Munchen, August 28th, 2012

30. All-Cause Mortality WOEST Triple therapy group Double therapy group
Days
Cumulative incidence of death 30 60 90
120
180
270
365
0 %
2.5 %
5 %
7.5 %
284
281
280
279
277
252
n at risk:
278
276
275
274
256
6.4%
2.6%
HR= %CI[ ]
p=0.027
Triple therapy group
Double therapy group
ESC, Hotline III, Munchen, August 28th, 2012

31. WARFARIN AND ANTIPLATELET DRUG IN PATIENTS SURVIVED ACUTE CORONARY SYNDROM
WOEST
WARFARIN + CLOPIDOGREL are better than WARFARIN +ASPIRIN +CLOPIDOGREL in the frequency of bleeding complications and similar in the rate of thrombotic events
PCI TREATMENT

32. What about adding novel oral anticoagulant to dual antiplatelet therapy in patients survived acute coronary syndrome?

33. Probability of TIMI major bleeding Probability of CVD/MI/Stroke
Apixaban with Antiplatelet therapy after Acute Coronary Syndrome (APPRAISE-2)
Randomized, double-blind controlled clinical trial comparing apixaban, at dose of 5 mg twice daiy with placebo in addition to standard antiplatelet therapy in pts with a recent ACS and at least 2 additional RF for recurrent ischemic events
Probability of TIMI major bleeding
Probability of CVD/MI/Stroke

34. Dabigatran vs. placebo in ACS patients with dual antiplatelet therapy
A randomized, double-blind, phase II trial
Probability of major and clinically relevant minor bleedings
Dabigatran, in a dose dependent manner, increases bleeding events during dual antiplatelet therapy

35. This dose is less than dose for patients with AF
Rivaroxaban in Patients with a Recent Acute Coronary Syndrome (ATLAS ACS 2-TIMI 51)
In pts with recent ACS Riva reduced risk of death from cardiovascular causes, MI or stroke.
Riva increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding
Double-blind, placebo-controlled trial
Patients with recent ACS, n=15526 (Api 2,5mg twice daily or Api 5 mg twice daily or placebo)
Mean follow-up - 13 months
Primary efficacy end point – CVD/MI/Stroke
BLEEDINGS
2,5 twice daily
N=5114
Placebo
N=5113
TIMI major not associated with CABG
65 (1,8%)
19 (0,6%)
TIMI minor
32 (0,9%)
20 (0,5%)
Intracranial
14 (0,4%)
5 (0,2%)
Fatal
6 (0,1%)
9 (0,2%)
This dose is less than dose for patients with AF
98,7% -intake aspirin
92,6% -intake clopidogrel

36. NEW ORAL ANTICOAGULANTS AS COMPONENTS OF TRIPLE THERAPY

37. Major bleeding rate (%/year)
Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in RELY Trial
WARF D D-110
Major bleeding rate (%/year)
18,113 pts with AF in RELY
6,952 pts (38,4%) also received an antiplatelet therapy during the study
5,789 pts on aspirin alone
351 pts on clopidogrel alone
812 pts on both drugs
Concomitant antiplatelet drugs appeared to increase the risk of major bleedings in RELY with no advantage of dabigatran over warfarin

39. These recent recommendations are based on expert consensus and observational trials and many questions do remain unanswered…

40. GENERAL RECOMMENDATIONS
Class
Level 1.
In AF patients stroke risk must be assessed using the CHA2DS2VASc score, and bleeding risk assessed using the HAS-BLED score. Risk stratification must be performed at regular intervals.
HAS-BLED score should be used to identify and correct potentially reversible bleeding risk factors
GRACE score should be used to stratify ACS risk I C 2.
If VKA is used good quality anticoagulation control is recommended with TTR>70% A 3.
When VKA is given in combination with clopidogrel and/or aspirin target INR 2,0-2,5
IIa 4.
Where a NOAC is used in combination with clopidogrel and/or low dose aspirin, the lower tested dose for stroke prevention in AF may be considered (dabi- 110mg b.I.d., riva- 15mg o.d., api-2,5 mg b.i.d.)
IIb 5.
In pts with AF and stable vascular disease (free from any acute ischaemic event or repeat revascularization >1 year) the patient should be managed with OAC alone (whether NOAC or VKA) B 6.
Radial access should be considered as the default for CAG/PCI to minimize the risk of access related bleeding depending on operator expertise and preference 7.
New generation DES may be preferred over BMS in pts at low risk of bleeding (HAS-BLED 0-2) 8.
Novel P2Y12 receptor inhibitors (prasugrel and ticagrelor) should not be part of triple therapy in pts with AF
III

41. SCHEME OF ANTITHROMBOTIC THERAPY IN PATIENTS WITH AF
In pts with stable angina and AF undergoing PCI at low bleeding risk TT should be given for a minimum of 4 weeks and no longer than 6 months after PCI, following with dual therapy with OAC(whether new or VKA) and clopidogrel (or aspirin) up to 12 month
*- Dual therapy with OAC+Clopi may be considered in selected pts
**- Asp may be considered in pts on dual therapy
***- Dual therapy (OAC+Asp/Clopi) may be considered in pts at very high risk of coronary event

42. SCHEME OF ANTITHROMBOTIC THERAPY IN PATIENTS WITH AF
*- Dual therapy with OAC+Clopi may be considered in selected pts
**- Asp may be considered in pts on dual therapy
***- Dual therapy (OAC+Asp/Clopi) may be considered in pts at very high risk of coronary event

43. NOAC trials are ongoing

44. CONCLUSIONS
The period of triple therapy should be as short as possible
The duration of triple therapy depends on a number of considerations: acute or elective PCI, HAS-BLED score, type of stent with preference for new generation of DES or BMS
Use aspirin in low doses: mg daily
Use clopidogrel as preferred P2Y12 inhibitor to more potent ticagrelor or prasugrel
OAC – well-controlled adjusted dose warfarin (INR 2,0-2,5; TTR>70%) or NOAC
Use BMS*, thus minimizing the duration of triple therapy
Use the radial approach thus minimizing the risk of bleeding at the access site
The optimal NOAC regimen for patients with AF and ACS or undergoing PCI has not been addressed by RCT
* - It is uncertain whether BMS use requires a shorter duration of dual therapy than new generation DES. New data on dual therapy cessation shows no difference between BMS and DES, especially with new generation stents.

46. Recommendation on the Management of patients on Oral Anticoagulation With ACS and/or Undergoing PCI
Risk Stratification and Balance (CHA2DS2-Vasc risk scores) for assessing the risk of stroke, and HAS-BLED to assess bleeding risk in pts with AF)

47. PHARMACOLOGY OF THE NOVEL ANTICOAGULANTS

48. Is it always necessary to avoid aspirin from the combinatory therapy?