Triple Antithrombotic Therapyin Cardiac Patients
Elizaveta P. Panchenko, MD,PhDCardiology Research and Production Center
MoscowRussian Federation
September 17, 2014
DisclosuresConsultancy fees or honoraria from
SANOFI, Takeda-NYCOMED, Boehringer Ingelheim,Pfizer, Bristol-Myers Squibb, Bayer, Lilly, AstraZeneca, GlaxoSmithKline, MEDICINES
Triple antithrombotic therapy
1. Aspirin 2. Р2Y12 antagonists: clopidogrel, prasugrel,
ticagrelor3. Oral anticoagulants: vitamin K antagonists,
dabigatran, apixaban, rivaroxaban
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
1. Analysis of 261 consecutive pts with AF undergoing CAG: The rate of CAD – 34% The need of PCI /CABG – 21%
2. The frequency of AF (Meta-analysis 120 566 pts from 10 clinical trials)
- in pts with STEMI – 8% - in pts with NSTE-ACS - 6,4%
3. 2-21% of pts with ACS have AF
1-Kralev et al., PLoSOne.2011;6:e24964.2-Lopes et al. Heart.2008;94:867-873.
3-Schmitt et al., EHJ.2009; 30:1038-104
COEXISTENCE OF CORONARY ARTERY DISEASE AND ATRIAL FIBRILLATION
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
Dual antiplatelet therapy Anticoagulant
Bleedings worsen the outcomes in patients receiving the antithrombotic therapy
Achilles' heel
BLEEDINGS SIGNIFICANTLY INCREASE THE RISK OF DEATH
OASIS-5 dataset
What do we know about the frequency of bleedings in patients
with antithrombotic therapy?
Major Bleedings In AF Patients Receiving Antithrombotic Therapy
Aspirin Aspirin + Clopidogrel Warfarin1,3%(ACTIVE-A)
1,2%(AVERROES)2,0% (ACTIVE-W) 1,5-3,0%
Randomized trials
ANTITHROMBOTIC THERAPY AND RISK OF BLEEDINGS IN PATIENTS WITH ATRIAL FIBRILLATION
Antithrombotic therapy HR 95% CIWarfarin 2,08 1,95-2,23Clopidogrel 1,57 1,37-1,81Aspirin 1,25 1,17-1,34Aspirin + Clopidogrel 1,68 1,44-1,97Warfarin+Aspirin 2,87 2,58-3,19Warfarin+Clopidogrel 2,74 2,14-3,51Warfarin+Aspirin+Clopidogrel 3,75 2,7-5,19
70,760 patients with AF (UKGPRD registry) 1993-2008 years follow up 10,850 patients had bleedings during follow up
Fatal and nonfatal bleedings* according to antithrombotic regimen in time periods following inclusion (Denmark register)
Lamberts M et al. Circulation. 2012;126:1185-1193
11480 pts with AF and MI/PCI between 2000-2009y. Mean age -75,6 y. Male -60,9%
*- reguiring hospitalisation
Triple-22,6%
VKA+ ASP/CLOPI - 20,3%
VKA
HOW TO MINIMIZE THE RISK OF BLEEDINGS?
1. To decrease the number of antithrombotic drugs
What do we know about efficacy and safety of antiplatelet drugs in prevention of
stroke in AF patients?
ASPIRIN IS SUPERIOR TO PLACEBO
STROKE PREVENTION IN ATRIAL FIBRILLATION
Major bleedings
Major Fatal0
60
120
180
240251
42
162
27
Clopi+Asp Pl+Asp
ОР (95%CI)1,56 (0.96-2.53)
р=0,07
%
RR (95%CI)1,57 (1.29-1,92)
р<0,001
2,0%
1,3%
0,2%0,3%
RR11%
р=0,01
RR28%
р<0,001
RR22%
р=0,08
%
7,554 pts with AF, those didn’t wish or couldn’t intake warfarin
33 countries, follow-up – 3,6 years
ASP+CLOPI are superior to ASP,
STROKE PREVENTION IN AF PATIENTSACTIVE-A
but induce more bleedings…
Connolly et all, N Engl J Med 2009;360:2066-78.
WARFARIN IS SUPERIOR TO ASPIRIN
STROKE PREVENTION IN ATRIAL FIBRILLATION
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%
The ACTIVE Writing Group Lancet 2006; 367:1903-12
Stroke + SE +MI +CVD
Warfarin is superior to CLOPI+ASP
WarfarinWarfarin
Clopi+AspClopi+Asp
STROKE PREVENTION IN ATRIAL FIBRILLATIONACTIVE-W
Ха
Thrombin
Rivaroxaban
Apixaban
Dabigatran
Edoxaban
Fibrin
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
VKAVKA
VKA
Apixaban is Superior to Aspirin
AVERROES
Stroke or Systemic Embolism Major Bleeding
Cum
ulati
ve H
azar
d
STROKE PREVENTION IN ATRIAL FIBRILLATION
5,599 pts with AF at increased risk of stroke to whom VKA therapy was unsuitable Randomization Apixaban 5mg twice daily or Aspirin 81-324 mg per day Mean follow up period 1,1 year
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
What do we know about efficacy and safety of warfarin in patients survived
acute coronary syndrome?
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)
WARFARIN in Patients Survived Acute Coronary Syndrome Conservative strategy of treatment, before
«clopidogrel era»
Major bleeding
WARIS II WARIS II 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
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
HOW TO MINIMIZE THE RISK OF BLEEDINGS?
1.To decrease the number of antithrombotic drugs
2.To choose the optimal combination of anticoagulant (VKA or novel oral anticoagulant) and antiplatelet drugs (aspirin or clopidogrel or aspirin+clopidogrel)
Is it suitable to withdraw aspirin from triple therapy (asp+clopi+VKA)
in patients after PCI?
Incidence of any bleedingCumulative incidence of death, MI, Stroke, TVR and stent thrombosis
W JM Dewilde et al., for the WOEST study investigators www.thelancet.com http://dx.dol.org/10/1016/S0140-6736(12)62177-1
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%
ESC, Hotline III, Munchen, August 28th, 2012
age75
male
t0acs
oacind3cat
des
Overall
FALSE
TRUE
no
yes
no
yes
AF/AFlut
Mechanical valve
Other
No
DES
200
79
50
234
195
86
162
25
47
90
194
284
194
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
IndicationOAC
Stenttype
Overall
Subgroup
<75 years
>75 years
female
male
no
yes
AF/AFlut
MechanicalvalveOther
BMS
DES
Triple
79
200
50
234
195
86
162
25
47
90
194
284
VKA+Clopi
82
194
65
214
207
69
164
24
48
94
184
279
P-value for interaction
0.9157
0.8217
0.7210
0.1116
0.7761
0.7894
double therapy better <=> triple therapy better0.1 0.4 1
Death, MI, Stroke, TVR and stent thrombosis (subgroup analysis)
WOEST
HR
All-Cause Mortality
Days
Cu
mu
lati
ve
in
cid
en
ce
of
de
ath
0 30 60 90 120 180 270 365
0 %
2.5 %
5 %
7.5 %
284 281 280 280 279 277 270 252n at risk: 279 278 276 276 276 275 274 256
6.4%
2.6%
HR=0.39 95%CI[0.16-0.93]
p=0.027
Triple therapy groupDouble therapy group
WOEST
ESC, Hotline III, Munchen, August 28th, 2012
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
What about adding novel oral anticoagulant to dual antiplatelet therapy
in patients survived acute coronary syndrome?
Apixaban with Antiplatelet therapy after Acute Coronary Syndrome (APPRAISE-2)
Probability of TIMI major bleedingProbability of CVD/MI/Stroke
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 major and clinically relevant minor bleedings
Dabigatran vs. placebo in ACS patients with dual antiplatelet therapy
A randomized, double-blind, phase II trial
Dabigatran, in a dose dependent manner, increases bleeding events during dual antiplatelet therapy
98,7% -intake aspirin92,6% -intake clopidogrel
This dose is less than dose for patients with
AF
BLEEDINGS 2,5 twice daily
N=5114
PlaceboN=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%)
Rivaroxaban in Patients with a Recent Acute Coronary Syndrome (ATLAS ACS 2-TIMI 51)
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
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
NEW ORAL ANTICOAGULANTS AS COMPONENTS OF TRIPLE THERAPY
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 Use of Antiplatelet Therapy with Dabigatran or Warfarin in RELY Trial
WARF D-150 D-1100 +1 +2 0 +1 +2 0 +1 +2
Major bleeding rate (%/year)
Concomitant antiplatelet drugs appeared to increase the risk of major bleedings in RELY with no advantage of dabigatran over warfarin
These recent recommendations are based on expert consensus and observational trials and many questions do remain
unanswered…
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.a) HAS-BLED score should be used to identify and correct potentially reversible bleeding risk factorsb) 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%
I A
3. When VKA is given in combination with clopidogrel and/or aspirin target INR 2,0-2,5
IIa C
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 C
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)
IIa 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
IIa C
7. New generation DES may be preferred over BMS in pts at low risk of bleeding (HAS-BLED 0-2)
IIb C
8. Novel P2Y12 receptor inhibitors (prasugrel and ticagrelor) should not be part of triple therapy in pts with AF
III C
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
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
NOAC trials are ongoing
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: 75-100 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.
CONCLUSIONS
PHARMACOLOGY OF THE NOVEL ANTICOAGULANTS
Is it always necessary to avoid aspirin from the combinatory therapy?
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