Transcript Slide 1

Adjunctive Antithrombotic for PCI
SCAI Fellows Course
December 9, 2013
Theodore A Bass, MD FSCAI
President SCAI
Professor of Medicine, University of Florida
Medical Director UF Shands CV Center,Jacksonville
Disclosures
Adjunctive Antithrombotic Therapy for PCI:
Theodore A. Bass MD, FSCAI
The following relationships exist related to this presentation

Consulting: none
ANTITHROMBOTIC DRUGS USED IN ACS/PCI
I. ANTIPLATELET DRUGS
• COX-1 inhibitor (aspirin)
• P2Y12 inhibitors (ticlopidine; clopidogrel; prasugrel; ticagrelor)
• Glycoprotein IIb/IIIa inhibitors (abciximab; eptifibatide; tirofiban)
II. ANTICOAGULANT DRUGS
• Anti-Factor II (anti-thrombins)
- Indirect Thrombin Inhibitors (UFH & LMWH)
- Direct Thrombin Inhibitors (Bivalirudin)
• Anti-Factor X
- Fondaparinux
ANTITHROMBOTIC DRUGS USED IN PCI
Many options! Who wins?
Optimal Antithrombotic PCI
“Cocktail”
• Stable CAD
• UA/NSTEMI
• STEMI
What’s MY Antithrombotic “Cocktail”
• Stable CAD elective PCI
Aspirin 325mg LD / 81mg maintenance
+
Clopidogrel 600mg LD / 75mg maintenance
+
UFH (70-100 IU/kg)
Primary Endpoint: CV Death, MI, Stent Thrombosis
High Platelet Reactivity
Observed event rates are listed; P value by log rank test.
Early termination of TRIGGER-PCI at
March 18, 2011
 236 patients completed 6 months follow-up
 Only 1 clinical endpoint (peri-procedural MI) observed
Event rate, %
→ rate 0.4%
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Non-CABG TIMI major, minor or minimal bleeding
Prasugrel
Clopidogrel
Hazard Ratio 1.517
(95% CI, 0.428-5.376)
p=0.516
0
30
60
90 120 150 180 210 240
Days from randomization
Trenk D. JACC 2012
Optimal Antithrombotic “Cocktail”
• Stable CAD
• UA/NSTEMI
• STEMI
Optimal Antithrombotic “Cocktail”
When to consider:
1. GP IIb/IIIa inhibitors
2. Bivalirudin
3. New P2Y12 receptor antagonists
NSTEMI: The Role of GP IIb/IIIa inhibitors in the
era of clopidogrel and direct thrombin inhibitors
Shifting the paradigm !!
“IIb or not IIb?”
Major Considerations:
1) Trials performed in the “good old days”
- Less experience; not all with stents; devices
2) Antiplatelet therapy
-
-
1st generation thienopyridine (ticlopidine)
300mg LD clopidogrel
3) Anticoagulant therapy
- indirect thrombin inhibitors
William Shakespeare
(1564- 1616)
ISAR-REACT 2: Abciximab vs. Placebo in ACS
All patients pretreated with 600mg clopidogrel at least 2 hrs prior to PCI.
20 Death/MI/UTVR, %
Troponin-Positive: RR=0.71 [0.54-0.95]
15
10
Abciximab vs. Placebo
5
Troponin-Negative: RR=0.99 [0.56-1.76]
0
0
5
10
15
20
25
30
Days after randomization
Kastrati et al. JAMA. 2006;295:1531-8.
Impact of MI and Major Bleeding (Non-CABG) in
the First 30 Days on Risk of Death Over 1 Year
ACUITY
1 Year Estimate
Both MI and Major Bleed (N=94)
Major Bleed Only (Without MI) (N=551)
MI Only (Without Major Bleed) (N=611)
No MI or Major Bleed (N=12,557)
Mortality (%)
30
28.9%
12.5%
8.6%
3.4%
25
20
15
10
5
0
0
30
60
90
120 150
180 210 240 270
300 330 360
Days From Randomization
Mehran R, et al. Eur Heart J. 2009;30(12):1457-1466.
390
ACUITY: Primary Results
UFH/Enox +
GP IIb/IIIa
Observed
Bivalirudin +
GP IIb/IIIa
Bivalirudin
alone
Rate
Rate
P
Value
Rate
P
Value
Net clinical
outcome
11.7%
11.8%
<0.001 NI
10.1%
0.015 Sup
Ischemic
events
7.3%
7.7%
0.007 NI
7.8%
0.011 NI
Major
bleeding
5.7%
5.3%
0.001 NI
3.0%
<0.001 Sup
Endpoint
NI = non-inferiority; Sup = superiority
Primary endpoint
ISAR-REACT 4
Death, large MI, uTVR, major bleeding
Cumulative Incidence (%)
20
Relative risk, 0.99 (95% CI, 0.74–1.32)
P=0.94
Abciximab 10.9%
Bivalirudin 11.0%
15
10
5
0
0
5
10
15
20
Days since Randomization
25
30
Kastrati et al. NEJM 2011
Secondary safety endpoint
ISAR-REACT 4
Major bleeding
Cumulative Incidence (%)
20
Relative risk, 1.82 (95% CI, 1.10–3.07)
P=0.02
15
10
Abciximab 4.6%
Bivalirudin 2.6%
5
0
0
5
10
15
20
Days since Randomization
25
30
Kastrati et al. NEJM 2011
What’s MY Antithrombotic “Cocktail”
• UA/NSTEMI PCI
Bivalirudin:
- High bleeding risk (elderly, CKD, diabetes)
- Pre-treated w/clopidogrel
- Unclear prior anticoagulation (safe to switch)
GPI:
- Already on upstream GPI
- Not pre-treated w/clopidogrel (especially if high
thrombotic burden)
- ACS while on DAPT
What’s MY Antithrombotic “Cocktail”
• UA/NSTEMI PCI
New P2Y12 Receptor Antagonists?
TRITON TIMI 38
(prasugrel vs clopidogrel)
PLATO
(ticagrelor vs clopidogrel)
TRITON vs PLATO: Is there a winner?
• Prasugrel and ticagrelor both showed favorable efficacy and
safety profiles in their respective trials and only a head-to-head
comparison will be able to define the winner.
• Subgroup analysis will allow to define their best niche.
– Prasugrel. Particularly efficacious in reducing stent
thrombosis, MI, uTVR and great benefit in diabetics and STEMI.
Contraindicated: high-risk bleeding; prior TIA/stroke
Considerations: elderly, low-weight; CABG/surgery (7days).
– Ticagrelor. Particularly efficacious in reducing mortality (offtarget effects), OK for patients with prior TIA/ ischemic stroke.
Contraindicated: high-risk bleeding; prior hemorrhagic stroke
Considerations: COPD/asthma, bradyarrythmia, gout
syndromes, advanced CKD, compliance (b.i.d. administration),
regional differences (North America?/ASA dose),
CABG/surgery (5-7days).
Optimal Antithrombotic PCI
“Cocktail”
• Stable CAD
• UA/NSTEMI
• STEMI
All-cause mortality or reinfarction (%)
3-Year All-Cause Mortality
or Reinfarction Landmark analysis
Heparin + GPIIb/IIIa (n=1802)
Bivalirudin (n=1800)
3-year HR (95% CI)
30-day HR (95% CI)
0.72 (0.58 – 0.91)
0.84 (0.61 – 1.16)
p=0.005 10.6%
p=0.30
5
4
3
7.8%
2
4.5%
3.8%
1
0
0
3
6
9
12
15
18
21
24
Months
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
27
30
33
36
Def/Prob Stent Thrombosis (%)
Stent Thrombosis 1-Day Landmark
Analysis: Impact of Antithrombin
Bivalirudin monotherapy
Heparin + GPIIb/IIIa inhibitor
3.5
3.0
HR [95%CI] =
5.93 [2.06-17.04]
2.5
P = 0.0002
3.0%
2.2%
2.0
1.5%
1.5
HR [95%CI] =
1.73 [0.47-1.13]
1.0
P = 0.06
0.5
0.3%
0.0
0
1
30
90
180
270
365
1485
1457
1355
1315
Time in Days
Number at risk
Bivalirudin
UFH+GPIIb/IIIa
1611 1600 1562
1591 1587 1521
1525
1495
1506
1476
Death, MI or Stroke in STEMI-PCI
P=0.02
%
P=0.07
P=0.11
Drug
Follow-up
N=6364
N=7544
N=3534
Double dose clopidogrel
Ticagrelor
Prasugrel
1 month
6-12 months
15 months
50
INFUSE-AMI: Infarct size at 30 days*
- Primary endpoint -
30
20
10
JAMA 2012
Infarct size, %LV
40
Median [IQR]
Median [IQR]
15.1%
17.9%
[6.8, 22.7]
[10.3, 25.4]
P=0.03
IC abciximab No abciximab
N=229
N=223
*Core laboratory assessed
What’s MY Antithrombotic Primary PCI
“Cocktail”
• STEMI (# 1)
Aspirin 325mg LD
+
Prasugrel 60mg LD
+
UFH (4000 IU)
What’s MY Antithrombotic Primary PCI
“Cocktail”
• STEMI (# 2)
Bivalirudin in all my Primary PCI patients.
Consider GPI:
-
STEMI while on DAPT
Already on upstream GPI
IC bolus only ? (INFUSE-AMI)
Bail-out
NOT in my Antithrombotic “Cocktail”
what’s not good for me, may be good for others…
…….it’s a matter of taste!
LMWH (enoxaparin) – STEEPLE, ATOLL
High maintenance dose clopidogrel - OASIS-7
Fondaparinux - OASIS-5, OASIS-6, OASIS-8
EMERGING ANTITHROMBOTIC DRUGS
I. ANTIPLATELET DRUGS
• Elinogrel – INNOVATE-PCI
• Vorapaxar – TRACER/TRA 2P
• Cangrelor
– CHAMPION PHOENIX, BRIDGE
II. ANTICOAGULANT DRUGS
• Otamixaban – TAO
• Rivaroxaban - ATLAS 2
Current Controversies on DAPT in PCI
• Which drug?
• When to start?
• Which dose?
• How long?
• Testing?
Current Controversies on DAPT in PCI
• Which drug?
• When to start?
• Which dose?
• How long?
• Testing?
Clopidogrel Genetic Testing
I IIa IIb III
Genetic testing might be considered to identify whether a
patient at high risk for poor clinical outcomes is
predisposed to inadequate platelet inhibition with
clopidogrel.
I IIa IIb III
When a patient predisposed to inadequate platelet
inhibition with clopidogrel is identified by genetic testing,
treatment with an alternate P2Y12 inhibitor (e.g., prasugrel
or ticagrelor) might be considered.
I IIa IIb III
No Benefit
The routine clinical use of genetic testing to screen
clopidogrel-treated patients undergoing PCI is not
recommended.
Platelet FunctionTesting
I IIa IIb III
Platelet function testing may be considered in
patients at high risk for poor clinical outcomes.
I IIa IIb III
In clopidogrel-treated patients with high platelet
reactivity, alternative agents, such as prasugrel
or ticagrelor, might be considered.
I IIa IIb III
No Benefit
The routine clinical use of platelet function
testing to screen clopidogrel-treated patients
undergoing PCI is not recommended.
Thank You