Transcript Как выбрать оптимальный антикоагулянт д

Triple Antithrombotic Therapy
in Cardiac Patients
Elizaveta P. Panchenko, MD,PhD
Cardiology Research and Production Center
Moscow
Russian Federation
September 17, 2014
Disclosures
Consultancy 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,
ticagrelor
3. 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
COEXISTENCE OF CORONARY ARTERY DISEASE AND
ATRIAL FIBRILLATION
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
BOTH DISEASES DEMAND
ANTITHROMBOTIC THERAPY
Acute Coronary
Syndrome
•Aspirin (forever)
•Р2Y12 inhibitor:
Clopidogrel, Prasugrel,
Ticagrelor (12 months)
Dual antiplatelet therapy
•
•
•
•
•
•
Atrial Fibrillation
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Aspirin
Aspirin+Clopidogrel
Anticoagulant
Achilles' heel
Bleedings worsen the outcomes
in patients receiving the
antithrombotic therapy
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
Randomized trials
Aspirin
1,3%(ACTIVE-A)
1,2%(AVERROES)
Aspirin + Clopidogrel
2,0% (ACTIVE-W)
Warfarin
1,5-3,0%
ANTITHROMBOTIC THERAPY AND RISK OF BLEEDINGS
IN PATIENTS WITH ATRIAL FIBRILLATION
 70,760 patients with AF (UKGPRD registry)
 1993-2008 years follow up
 10,850 patients had bleedings during follow up
Antithrombotic therapy
Warfarin
HR
2,08
95% CI
1,95-2,23
Clopidogrel
Aspirin
Aspirin + Clopidogrel
Warfarin+Aspirin
1,57
1,25
1,68
2,87
1,37-1,81
1,17-1,34
1,44-1,97
2,58-3,19
Warfarin+Clopidogrel
Warfarin+Aspirin+Clopidogrel
2,74
3,75
2,14-3,51
2,7-5,19
Fatal and nonfatal bleedings* according to antithrombotic
regimen in time periods following inclusion (Denmark register)
 11480 pts with AF and MI/PCI between 2000-2009y.
 Mean age -75,6 y.
 Male -60,9%
Triple-22,6%
VKA+ ASP/CLOPI - 20,3%
VKA
*- reguiring hospitalisation
Lamberts M et al. Circulation. 2012;126:1185-1193
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?
STROKE PREVENTION IN ATRIAL FIBRILLATION
ASPIRIN IS SUPERIOR TO PLACEBO
STROKE PREVENTION IN AF PATIENTS
ACTIVE-A
ASP+CLOPI are superior to ASP,
but induce more bleedings…
 7,554 pts with AF, those didn’t wish or
couldn’t intake warfarin
 33 countries, follow-up – 3,6 years
Major bleedings
%
240
%
251
Clopi+Asp
Pl+Asp
2,0%
180
162
1,3%
120
RR
22%
р=0,08
RR
11%
р=0,01
60
RR
28%
р<0,001
0
ОР (95%CI)
1,56 (0.96-2.53)
р=0,07
42
RR (95%CI)
1,57 (1.29-1,92)
р<0,001
Major
Connolly et all, N Engl J Med 2009;360:2066-78.
0,3%
27
0,2%
Fatal
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%
STROKE PREVENTION IN ATRIAL FIBRILLATION
ACTIVE-W
Warfarin is superior to CLOPI+ASP
Stroke + SE +MI +CVD
Clopi+Asp
Warfarin
Clopi+Asp
Warfarin
The ACTIVE Writing Group Lancet 2006; 367:1903-12
VKA
 The NOACs fall into two classes:
the oral direct thrombin
inhibitors (dabigatran) and oral
direct factor Xa inhibitors
(rivaroxaban, apixaban,
edoxaban)
VKA
VKA
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
Ха
Rivaroxaban
Apixaban
Thrombin
Dabigatran
Fibrin
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 81-324 mg per day
Mean follow up period 1,1 year
Cumulative Hazard
Stroke or Systemic Embolism
AVERROES
Major Bleeding
 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 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
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?
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%
Incidence of any bleeding
Cumulative 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
WOEST
Death, MI, Stroke, TVR and stent thrombosis (subgroup analysis)
Factor
Age
age75
Gender
male
ACS
t0acs
Subgroup
Triple
HR
VKA+Clopi
<75 years
FALSE
TRUE
>75
years
79 194 82
200
79 82 194
200
0.9157
0.9157
female
no
yes
male
50 65 65
234 214214
0.8217
0.8217
no
yes
195 207207
86 69 0.721
69
0.7210
162
Indication
oacind3catAF/AFlut
AF/AFlut
162 164164
Mechanical
OAC
25 24 0.1116
24
Mechanical valve
valve
Other
47 48 0.7761
47
48
Other
Stent
des
type
Overall
Overall
P-value for interaction
BMS
No
DES
0.1116
0.7761
90 94 94
194 184184
0.7894
0.7894
284 279279
0.1
0.4
1
double therapy better <=> triple therapy better
ESC, Hotline III, Munchen, August 28th, 2012
WOEST
All-Cause Mortality
Triple therapy group
Double therapy group
Cumulative incidence of death
7.5 %
6.4%
HR=0.39 95%CI[0.16-0.93]
5%
p=0.027
2.6%
2.5 %
0%
0
30
60
90
120
180
270
365
270
274
252
256
Days
n at risk:
284 281 280 280 279
279 278 276 276 276
ESC, Hotline III, Munchen, August 28th, 2012
277
275
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)
 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
CVD/MI/Stroke
Probability of TIMI major bleeding
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
Rivaroxaban in Patients with a Recent Acute
Coronary Syndrome (ATLAS ACS 2-TIMI 51)
 Double-blind,
placebo-controlled
trial risk of death from cardiovascular causes, MI or stroke.
In
pts
with
recent
ACS
Riva
reduced
 Patients with recent ACS, n=15526 (Api 2,5mg twice daily or Api 5 mg twice daily or placebo)
Riva
increased
the- 13
risk
of major bleeding and intracranial hemorrhage but not the risk of
 Mean
follow-up
months
 Primary
efficacy end point – CVD/MI/Stroke
fatal
bleeding
98,7% -intake aspirin
92,6% -intake clopidogrel
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
NEW ORAL ANTICOAGULANTS
AS COMPONENTS OF TRIPLE THERAPY
Concomitant Use of Antiplatelet Therapy with
Dabigatran or Warfarin in RELY Trial
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
0 +1 +2 0 +1 +2 0 +1 +2
WARF
D-150
D-110
 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…
1.
2.
3.
4.
5.
6.
7.
8.
GENERAL RECOMMENDATIONS
Class
Level
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 factors
b) GRACE score should be used to stratify ACS risk
If VKA is used good quality anticoagulation control is recommended
with TTR>70%
When VKA is given in combination with clopidogrel and/or aspirin
target INR 2,0-2,5
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.)
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)
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
New generation DES may be preferred over BMS in pts at low risk of
bleeding (HAS-BLED 0-2)
Novel P2Y12 receptor inhibitors (prasugrel and ticagrelor) should not
be part of triple therapy in pts with AF
I
C
I
A
IIa
C
IIb
C
IIa
B
IIa
C
IIb
C
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
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: 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.
PHARMACOLOGY OF THE NOVEL ANTICOAGULANTS
Is it always necessary to
avoid aspirin from the
combinatory therapy?