Adjunctive Pharmacology in the
Cardiac Catheterization
Laboratory
Parul B. Patel, MD
April 28, 2012
Antiplatelet
• Aspirin
• Thienopyridines
• Novel P2Y12 ADP
Receptor Antagonists
• Glycoprotein IIb/IIIa
inhibitors
– IV
– Oral
Antithrombotic
• Unfractionated heparin
• Low molecular weight
heparin
• Fondaparinux
• Direct thrombin
inhibitors
Goal of Therapy
• Improving 30-day outcomes
– Thrombosis/ vessel occlusion
– Periprocedural MI
• Avoidance of bleeding complications
• No significant effect on restenosis
Intact Endothelium Maintains
Inactive Platelets
• Smooth discs maintained in inactive state by endothelial secretion of NO and prostacyclin (PGI2), and ADP conversion to adenosine
(Bhatt. NEJM 2007)
Platelet Activation in Vascular Injury
• Exposure to extracellular matrix at sites of injury causes platelet activation and adherence
• Release of prothrombotic factors ADP and TXA2
• Cross-linking via fibrinogen leads to platelet aggregates
(Bhatt. NEJM 2007)
Platelet Activation during PCI
• Coronary sinus sampling pre and post PTCA
demonstrated markers of platelet activation (Gasperetti et al. Circulation 1993)
• Angioscopic studies of stent thrombosis showed
white (platelet-rich) thrombus ( Topol, Serruys. Circulation 1998)
• Reduced markers of platelet aggregation observed with ASA/ticlopidine combination compared to
control (Gregorini et al. JACC 1997) (Gawaz et al. Circulation 1996)
• Retrospective study of 220 patients post
successful PTCA – No thrombus at beginning of procedure
– >98% given at least 10,000 units heparin
• Observed for 30 minutes
• Repeat angiography: 15% had thrombus
• No ASA pretreatment (n=121): 21.8%
• Pretreatment ASA (n=110): : 12.5% (p=0.19)
• Pre-treatment dipyridamole + ASA (n=32): 8.2% (p=0.01)
(Barnathan et al. Circulation 1987)
Importance of Platelet Inhibition During PCI
Aspirin and Dipyridamole in the Prevention of
Re-Stenosis after Percutaneous Transluminal
Coronary Angioplasty
• 376 patients randomized to either aspirin +
dipyridamole vs. placebo 24 hours prior to
PCI and thereafter
• Follow-up angiography in 249 pts. 4-7
months after
– No effect on restenosis
• Periprocedural Q-wave MI among 376 pts:
– Placebo: 6.9%
– Pre-treatment: 1.6% (P=0.0113)
(Schwartz et al. NEJM 1988)
Historical Perspective: Coronary Stenting
and Importance of Platelet Inhibition
• Self-expandable stents first used in acute or
threatened closure in the setting of PTCA
• Complete occlusion of stent seen on follow up
angiography in 27/117 stents (23%),
8 deaths (7.6%) (Serruys et al. NEJM 1991)
• Balloon-expandable stents with ASA pretreatment
and aggressive anticoagulation reduced acute stent
thrombosis to ~3.5% (Fischman et al. NEJM 1994; Serruys et al NEJM
1994)
1994 Coronary Stenting
Standard of Care • ASA 325 mg
• Dipyridamole 75 mg TID
• Heparin 10,000 units IV (post access)
• Dextran infusion during procedure
• Heparin held to pull sheath, then immediately restarted
• Warfarin afterwards, with heparin IV until INR therapeutic
• Warfarin (1-3mon), ASA (3 mon-indefinitely) , Dipyridamole (1-6 months) (Fischman et al. NEJM 1994)
(Serruys et al. NEJM 1994)
(Sutton et al. Circulation 1994)
Improved Results with
Antiplatelet Agents
• High bleeding
complication risk with
post-procedure
anticoagulation (7-14%)
• Long in-hospital stay
•Aggressive anticoagulation
abandoned
• Improved stent deployment technique
• Antiplatelet therapy
•Acute stent thrombosis risk decreased to <1%
(Colombo et al. Circulation 1995)
Aspirin: Mechanism of
Antiplatelet Effect • Permanent inactivation of prostaglandin G/H
synthase (COX)
– Ultimately, inhibits thromboxane production
• Thromboxane A2 is a potent amplifier of platelet aggregation and a vasoconstrictor
• Other mechanisms for usefulness in CAD:
– Enhanced NO mediated platelet inhibition
– Increased fibrinolytic activity, and decreased plasma coagulation (Bhatt et al. Circ Research 2007)
• Clinical effect: prolonged bleeding time
(Awtry et al. Circulation 2000)
Prostaglandin Production
Inhibited
by ASA
Aspirin Dose and Bleeding
(Serebruany et al. Am J Cardiol 2005)
Meta-analysis of 192,036
pts in 31 clinical trials
Aspirin doses <100 mg
with lowest bleeding rate
Patients already taking daily aspirin therapy
should take 81 to 325 mg prior to PCI.
Patients not on aspirin therapy should be
given nonenteric aspirin 325 mg prior to PCI.
I IIa IIb III
I IIa IIb III
(Levine et al. JACC 2011)
ACC/AHA Guideline for Aspirin during PCI
After PCI, aspirin should be continued
indefinitely.
After PCI, it is reasonable to use 81 mg per
day of aspirin in preference to higher
maintenance doses.
I IIa IIb III
I IIa IIb III
(Levine et al. JACC 2011)
ACC/AHA Guideline for Aspirin during PCI
An anticoagulant should be administered
to patients undergoing PCI.
Prevents thrombus formation at site of
injury and on guidewires and catheters
ACC/AHA Guideline for Anticoagulant
Therapy: Use of Parenteral
Anticoagulants During PCI
I IIa IIb III
(Levine et al. JACC 2011)
Unfractionated Heparin
• Sulfated polysaccharide
• Weight 3,000 to 30,000 Da
• Inactivates thrombin and factor Xa via
antithrombin-dependent pathway
– Inhibits fibrin formation
– Inhibits thrombin-induced activation of
platelets
• Disadvantages:
– Propensity to bind other proteins and cells
• Variable response; ‘heparin resistance’
Unfractionated Heparin
• “Standard of care by default”
• Most frequently used antithrombotic agent in PCI
– Low cost
– Activated clotting time (ACT) used to measure effect
– Antagonist available (protamine)
• Disadvantages:
– Propensity to bind other proteins and cells
• Variable response; ‘heparin resistance’
– Inability to bind thrombin bound to fibrin or
subendothelial surfaces
– Thrombocytopenia
Defining the Optimal Activated Clotting Time During
Percutaneous Coronary Intervention
Aggregate Results From 6 Randomized, Controlled Trials
• N = 5,216
• All with heparin dose >100 units/kg
• ACT 350-375 s to be associated with lowest composite ischemic/bleeding event rate (6.6%)
– Linear increase in bleeding after ACT > 350 s
(Chew et al. Circulation 2001)
Relationship Between Activated Clotting Time
and Ischemic or Hemorrhagic Complications
• 8,369 patients with data on ACT, ischemic and hemorrhagic
events at 48 hours (median ACT 297 sec)
• Ischemic events not correlated with maximal procedural ACT
• Incidence of major or minor bleeding increased by ACT
quartile
• Linear increase in bleeding as ACT approached 365 s
• Increase in bleeding with higher total heparin dose
– Lower weight, older, female gender associated with increased
bleeding
(Brener et al. Circulation 2004)
Analysis of 4 Recent Randomized Clinical Trials of
Percutaneous Coronary Intervention
Ischemic Events by ACT
Quartiles at 48 hours
(Brener et al. Circulation 2004)
Incidence of Bleeding Events by
ACT Quartiles
(Brener et al. Circulation 2004)
Contemporary Heparin Dosing
• Suggested dosing:
– Without GP IIb/IIIa inhibitor, 70-100U/kg
• target ACT Hemotech 250-300 s, Hemochron 300-350
– GP IIb/IIIa inhibitor, 50-70 U/kg
• target ACT 200-250
• Sheath removal ACT less than 150-180 s
I IIa IIb III
Administration of intravenous UFH is
useful in patients undergoing PCI.
(Levine et al. JACC 2011)
Low-Molecular Weight Heparin
• Short-chain polysaccharide
• Theoretical benefit is more consistent, predictable anti-Xa activity
– Xa activates prothrombin thrombin
• Anti factor Xa:IIa ratio >2.0
• Enoxaparin most widely studied
Low-Molecular Weight Heparin
• Lower risk ACS trials with conservative strategy
– ESSENCE (n~3,000) treated 2-8 days
– TIMI 11B (n~4,000)
– Significant reduction in death/MI compared to unfractionated heparin
Enoxaparin use in Invasive
Mangement of ACS
• More recent trials in which ACS patients
managed invasively
– A to Z (n~ 4,000 pts) (Blazing et al. JAMA 2004)
• All pts treated with tirofiban
• 80% enzyme positive
• 60% underwent cath or PCI
• Enoxaparin found to be noninferior to UFH in terms
of preventing death/MI/recurrent ischemia as well as
bleeding.
– SYNERGY (n~10,000) (Mahaffey et al. JAMA 2004)
SYNERGY
• High-risk pts with intended invasive strategy
randomized to enoxaparin vs. UFH
• 92% underwent cath
– 47% underwent PCI
– 19% CABG
• ~60% treated with GP IIb/IIIa inhibitor
• ~65% treated with thienopyridine
(Mahaffey et al. JAMA 2004)
SYNERGY
No difference in nonfatal MI or death at 30 days
(14 vs. 14.5% with UFH) (Mahaffey et al. JAMA 2004)
SYNERGY
• Increased TIMI major bleeding with
enoxaparin 9.1 % vs. 7.6% with UFH
– Intracranial bleed, hemodynamically
compromising bleed similar.
• 75% pts treated with antithrombotic therapy
prior to randomization
– For ‘crossovers’ transfusion rate 30-35%,
double that of no crossover.
– Death or MI also increased in crossovers
(Mahaffey et al. JAMA 2004)
Enoxaparin in PCI: Conclusions
• Can be used as alternative to UFH in ACS:
‘established efficacy’ (ACC/AHA class I, LOE A)
• Switching anticoagulants not recommended
• ACT not reliable
– Manual hemostasis: 6-8 hours after last SQ dose, 4
hours after last IV dose
• Not fully reversed with protamine
– May need to repeat dose as t1/2 of protamine is
shorter
ACC/AHA Guideline for Enoxaparin
during PCI
I IIa IIb III An additional dose of 0.3 mg/kg intravenous enoxaparin
should be administered at the time of PCI to patients who
have received <2 therapeutic subcutaneous doses (e.g., 1
mg/kg) or received the last subcutaneous enoxaparin dose
8 to12 hours prior to PCI.
Performance of PCI with enoxaparin may be reasonable in
patients either treated with “upstream” subcutaneous
enoxaparin for UA/NSTEMI or who have not received
prior antithrombin therapy and are administered
intravenous enoxaparin at the time of PCI.
UFH should not be given to patients already
receiving therapeutic subcutaneous
enoxaparin.
I IIa IIb III
I IIa IIb III
Harm
(Levine et al. JACC 2011)
Fondaparinux
• Synthetic factor Xa inhibitor
– Once daily dosing (PT/PTT insensitive)
– Efficacy in DVT prophylaxis in orthopedic
surgery, and treatment of DVT or PE
– Maximum effect at 3 hours, half-life 17-21 hours
– Not for CrCl <30 ml/min
– Thrombocytopenia 0.5%
• Studied in ACS and STEMI
(Mehta et al. Circulation 2008)
OASIS 5
• N~20,000 with ACS
• 60% of ACS patients taken to cath lab, 34%
underwent PCI (~6,000 pts)
– Similar rates of death or MI at 30 days
compared with enoxaparin (~7%)
– Less major bleeding, access complications
• (2.2 vs. 4.1%), (3.3 vs. 8.1%)
– More catheter-associated thrombus
• (0.9 vs. 0.4%)
Yusuf et al. NEJM 2006
OASIS 6
• STEMI study of ~12,000 pts, ~4,000 of which
underwent primary PCI
• Death, MI or severe bleeding no different vs. UFH
• 16% GP IIb/IIIa inhibitor use
• Higher rate of guiding catheter thrombosis (0 vs. 22),
coronary complications (225 vs. 270) if only
fondaparinux used
(Yusuf et al. JAMA 2006)
Fondaparinux in PCI
• Preferred agent in ACS patients treated with
conservative strategy with high risk of
bleeding (ACC/AHA Class I, LOE B)
I IIa IIb III
• NOT ideal for PCI
Fondaparinux should not be used as the sole
anticoagulant to support PCI. An additional
anticoagulant with anti-IIa activity should be
administered because of the risk of catheter
thrombosis
Harm
(Levine et al. JACC 2011)
Bivalirudin • Direct thrombin inhibitor with t ½ 25
minutes
– Dose adjust for CrCl < 30
– Argatroban and hirudin have also been studied
as alternatives to heparin
• Theoretically superior to heparin as also
inhibits clot-bound thrombin
• Found to be non-inferior to heparin + GP
IIb/IIIa inhibitor in reducing ischemic
events in PCI for stable patients, ACS and
STEMI
Bivalirudin PCI Trials
• Generally compared against heparin + GP
IIB/IIIa inhibitor
• REPLACE 2: elective or urgent PCI
– N~ 6,000
– Major bleeding + ischemic events noninferior
– Major bleeding lower with bivalirudin 4.1% 2.4%
– Small, nonsignificant increase in periprocedural MI
(6.7% vs. 6.2%)
(Lincoff et al. JAMA 2004)
Bivalirudin PCI Trials
• ACUITY: PCI in moderate to high risk ACS
– n~ 14,000 with ACS, ~8,000 underwent PCI
– Overall, bivalirudin alone noninferior to heparin
+ GP IIb/IIIa inhibitor in ischemic events
– Bivalirudin alone superior in terms of major
bleeding (4% vs. 7%, p<0.0001)
– Post-hoc analysis showed greater ischemic events
unless pretreated with clopidogrel (14.1% vs.
8.5%) (Linkoff et al. JACC Cardiovasc Interv 2008)
(Stone et al. Lancet 2007)
Bivalirudin PCI Trials
• HORIZONS-AMI: PCI in STEMI pts
– n~3,600
• UFH bolus dose 60 units/kg + GP IIb/IIIa inhibitor
• All pretreated with clopidogrel (300 or 600mg)
– Bivalirudin alone with combined less bleeding +
ischemic events and less all-cause death (2.1% vs.
3.1% p=0.47)
– Increased 24-hr stent thrombosis with bivalirudin
alone (1.0% vs. 1.3% p <0.001)
• Stent thrombosis similar at 30 days
(Stone et al. NEJM 2008)
Bivalirudin Conclusions
• Less bleeding, but increased early ischemic
events suggest that bivalirudin is a less
potent antithrombotic agent compared to
heparin + GP IIb/IIIa inhibitor
• Useful in patients pretreated with
thienopyridine and/or high risk of bleeding
when GP IIb/IIIa inhibitor use not
anticipated
ACC/AHA Guideline for Bivalirudin
and Argatroban during PCI
(Levine et al. JACC 2011)
I IIa IIb III
I IIa IIb III
For patients undergoing PCI, bivalirudin
is useful as an anticoagulant with or
without prior treatment with UFH.
For patients with heparin-induced
thrombocytopenia, it is recommended
that bivalirudin or argatroban be used to
replace UFH.
P2Y12 ADP Receptor Antagonists
• ‘Thienopyridines’
– 1st gen: ticlopidine
– 2nd gen: clopidogrel
– 3rd gen: prasugrel
• Irreversibly bind P2Y12
– Multitude inhibitory effects on platelets
• Fibrinogen receptor activation, platelet degranulation, formation of platelet-leukocyte conjugates
• All are prodrugs requiring oxidation by hepatic cytochrome P450
Dual anti-platelet therapy consistently superior to ASA alone or ASA + warfarin
( Topol, Serruys. Circulation 1998)
Patients should be counseled on the need for and risks of DAPT before placement of intracoronary stents, especially a DES, and alternative therapies should be pursued if they are unwilling or unable to comply with the recommended duration of DAPT.
PCI with coronary stenting (BMS or DES) should not be performed if the patient is not likely to be able to tolerate and comply with DAPT for the appropriate duration of treatment based on the type of stent implanted.
Dual Antiplatelet Therapy Compliance
and Stent Thrombosis
Harm
I IIa IIb III
(Levine et al. JACC 2011)
I IIa IIb III
Ticlopidine
• Equivalent to ASA in preventing complications after PTCA (White et al. Circulation 1987)
– Also as effective in stroke prevention, acute MI, unstable angina
• Requires dosing at least 24 hours prior to stenting procedure for maximal effect
– Lowest incidence of MI seen when given >72 hrs prior to stenting
• Undesirable side effect profile
Ticlopidine Safety Profile
• GI symptoms 20%
• Cutaneous rashes 4.8-15%
• Severe neutropenia (granulocyte count < 450/ L) up to 1% (Bellavance et al. Stroke 1993)
• Fatal episodes of thrombotic thrombocytopenic purpura (survival rate 67%) (Bennett et al. Ann of Int Med 1998)
Peak incidence of hematologic effects at 3-8 weeks
Clopidogrel
• Found to be effective in multiple cardiovascular conditions
– Invasive and non-invasive treatment of ACS, acute STEMI, lone therapy in secondary prevention of vascular events
• Rapid onset of action with loading dose
• Overall, safety profile favorable
– Rare cases of TTP and HUS have been reported
– Bleeding risk similar to ASA 325mg in CAPRIE (Lancet 1996)
• Widely adopted into PCI protocols by Interventionalists
Meta-Analysis: 30-day MACE
Ticlopidine vs. Clopidogrel After Stenting
Concluded that clopidogrel better at reducing 30-day MACE
RCTs
(Bhatt et al. JACC 2002)
Registry
data
• PCI in ~2,600 ACS patients
• Median 10 days pretreatment ASA + 300 mg clopidogrel in study group
• All: dual antiplatelet therapy 30 days
• Pretreated group additional mean 8 months
• GP IIb/IIIa use ~25%
30-day CV death/ MI/ UTVR lowered
4.5% vs. 6.4% (p=0.03) (Mehta et al. Lancet 2001)
PCI-CURE: Follow-up
• No increase in major bleeding, but increased minor
bleeding leading to interruption (3.5% vs. 2.1%, p=0.03)
Reduction in
cardiovascular death/
MI with prolonged
treatment
(Mehta et al. Lancet 2001)
p=0.002
Clopidogrel
Placebo
• 2,116 pts for elective PCI from 99 North American centers (1999-2001)
(CREDO Investigators: Steinhubl et al. JAMA 2002)
ASA 325mg + clopidogrel 300mg
n=1053
ASA 325mg + clopidogrel 75mg
ASA 325mg + placebo
n=1063 Pre-procedure:
Day 1-28:
Day 28-12 mon: ASA 81-325mg
+ clopidogrel 75mg
ASA 81-325mg
+ placebo
Combined End Point at 28 days
Load > 6 hours prior
Load 3- 6 hours (51%)
No Pretreatment
(CREDO Investigators: Steinhubl et al. JAMA 2002)
• Non-significant 18.5% RRR for all pre-treated (p=0.23)
• 38.6% RRR if pretreatment > 6 hours (p=0.51)
Continued treatment after day 29 associated with further
RRR 37.4% in the combined endpoint (p=0.4)
Combined End Point Results at 1 year
Clopidogrel
Placebo
(CREDO Investigators: Steinhubl et al. JAMA 2002)
Bleeding at 28 Days
• No significant difference in major bleeding
• Trend towards minor bleeding if GpIIb/IIIa inhibitor use (p=0.08)
(CREDO Investigators: Steinhubl et al. JAMA 2002)
CREDO: Earlier Pre-Treatment Better
• Statistically significant reduction only seen when pre-treatment > 15 hours
• Continued incremental benefit up to 24 hours pretreatment
Log odds of
Death/MI/Urgent TVR
(CREDO Investigators: Steinhubl et al. JACC 2006)
15 hrs pretreated
placebo
Combined End Point at 28 days
8.3%
7.8%
3.5%
(CREDO Investigators: Steinhubl et al. JACC 2006)
Death/ MI/ UTVR %
Clopidogrel Conclusions
• Loading dose beneficial prior to PCI – 300 mg: at least 15 hours
– 600mg: at least 2 hours
– Limited benefit from higher loading doses as limited by
absorption
• CABG related bleeding risk is increased if
administered within 5 days
• Longer term therapy beneficial post–PCI, but
> 1% increase in bleeding – Concomitant PPI recommended if high risk
A loading dose of clopidogrel, generally 600 mg,
should be administered before or when PCI is performed.
In patients undergoing PCI within 12 to 24 hours of
receiving fibrinolytic therapy, a clopidogrel oral loading dose of 300 mg may be considered.
For all post-PCI stented patients receiving a DES, clopidogrel 75 mg daily should be given for at least 12 months if not at high risk of bleeding.
For post-PCI patients receiving BMS, clopidogrel
should be given for a minimum of 1 month and ideally up to 12 months (unless at increased risk of bleeding; then it should be given for two weeks).
I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III
I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III
I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III
I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III
ACC/AHA Guideline for
Clopidogrel during PCI
(Levine et al. JACC 2011)
Antiplatelet Therapy Resistance • Most common cause of treatment failure is
noncompliance
• APT resistance related to absence of platelet inhibition despite treatment
• Correlation between APT resistance and clinical events has been demonstrated in CVD, peripheral vascular disease, and stable CAD patients
Testing for APT Resistance
• Many tests – Bleeding Time
– Urinary thromboxane metabolite (11-dihydroxy thromboxane B2)
– Flow Cytometry (platelet-monocyte aggregates, P-selectin expression)
– Light Transmittance Aggregometry (ADP)
• Most recent clinical studies have used light
transmittance aggregometry (LTA)
– Not practical, but considered ‘gold standard’
Clopidogrel Resistance
• Demonstrated more often and more consistently using LTA studies.
• Variable rates of non-responsiveness depending on definition, test
– Range 5-44%
• Clinically, higher on-treatment reactivity has been associated with increased CK-MB, increased ST, increased MACE
(Angiolillo et al. Am J Cardiol 2005)
Distribution of platelet aggregation among
82 stable patients on chronic dual APT
Distribution of residual platelet
aggregation in 544 patients after
clopidogrel 300 mg
(Serebruany et al. Am J Cardiol 2005)
Various factors influencing platelet reactivity
and clinical events during clopidogrel therapy
(Gurbel P A et al. Eur Heart J 2012)
Relation of Clopidogrel Nonresponsiveness to
Clinical Outcomes
Gurbel et al. JACC 2007
Evidence for a Possible Threshold for
Ischemic Events After Elective Stenting
Gurbel et al. JACC 2007
40-50% platelet
aggregation
Platelet function testing may be considered in
patients at high risk for poor clinical outcomes.
In clopidogrel-treated patients with high platelet
reactivity, alternative agents, such as prasugrel or
ticagrelor, might be considered.
The routine clinical use of platelet function
testing to screen clopidogrel-treated patients
undergoing PCI is not recommended.
ACC/AHA Guideline on Platelet
FunctionTesting
I IIa IIb III
No Benefit
I IIa IIb III
I IIa IIb III
(Levine et al. JACC 2011)
Prasugrel
• 3rd generation thienopyridine
• Compared to clopidogrel:
– More rapid onset (15 minutes)
• (max effect within 60 minutes)
– More potent antiplatelet effect
– Less interpatient variability
• Antiplatelet effects studied in ASA-treated
patients with CAD
Angiolillo et al. Am Heart J 2008
• Study of 13,608 ACS patients with scheduled PCI – 99% underwent PCI
– 94% with stent (47% DES)
• 300 mg clopidogrel vs. 60 mg prasugrel
– 24 hrs prior - 1 hr post PCI
– Excluded prior thienopyridine use and increased bleeding risk
• Primary end point: CV Death/ MI/ U TVR
• 74% received study drug during or after PCI
– 54% GP IIb/IIIa inhibitor use ( Wiviott et al. NEJM 2007)
TRITON–TIMI 38 Investigators
Major End Points at 15 months
End Point Prasugrel
(N=6813)
Clopidogrel
(N=6795)
P Value
CV Death/ MI/ stroke 643 (9.9%) 781 (12.1%) < 0.001
CV Death 133 (2.1%) 150 (2.4%) 0.31
Non-fatal MI 475 (7.3)% 620 (9.5%) < 0.001
Non-fatal stroke 61 (1.0%) 60 (1.0%) 0.93
Death 188 (3.0%) 197 (3.2%) 0.64
U TVR 156 (2.5%) 233 (3.7%) < 0.001
Stent Thrombosis 688 (1.1%) 142 (2.4%) < 0.001
( Wiviott et al. NEJM 2007)
Bleeding Increased with Prasugrel
• TIMI major hemorrhage not related to CABG:
– Prasugrel 146 (2.4%)
– Clopidogrel 111 (1.8) (P=0.03)
• CABG major bleeding 13.4% vs. 3.2% (P<0.001)
• Life-threatening bleed 1.4% vs. 0.9% (P=0.01)
• Fatal TIMI major bleeding 0.4% vs. 0.1% (P=0.002)
• Intracranial hemorrhage 0.3% both groups
( Wiviott et al. NEJM 2007)
Cumulative Kaplan-Meier Estimates of
Key Study End Points
Primary Efficacy End Point
Key Safety End Point
( Wiviott et al. NEJM 2007)
TRITON-TIMI 38 Conclusions
• 2.3% reduction in MI
• 0.6% increase in TIMI major bleed
• Hx of stroke/TIA
• Age >75 yrs
• Weight < 60 kg
For every 1000 patients treated, 23 MIs prevented with
an excess of 6 non-CABG related TIMI major
hemorrhages.
No overall difference in cardiovascular mortality.
Compared to treatment with approved clopidogrel
loading and maintenance therapy:
( Wiviott et al. NEJM 2007)
Prasugrel should not be administered
in patients with a prior history of
stroke or TIA.
I IIa IIb III
(Levine et al. JACC 2011)
ACC/AHA Caution for Prasugrel Use
• Prasugrel not recommended in age > 75
years due to increased bleeding and lack of
benefit except in diabetics and patients with
prior MI
• Prasugrel not studied in elective PCI
Novel P2Y12 ADP Receptor Antagonists
• CPTPs (cyclo-pentyl-triazolo-pyrimidines)
– Reversible receptor antagonism
– Do not require conversion to active metabolite
• Ticagrelor
– Oral agent
– More potent and consistent platelet inhibition
– t ½ 6-13 hours
• 18,624 pts with ACS with or without ST-
segment elevation
• Ticagrelor 180mg load, then 90mg bid Versus
Clopidogrel 300mg , then 75mg qd
• 46% in each group received clopidogrel
prior to randomization
• Index event PCI in 61%, CABG in ~4.5%
PLATO Investigators
( Wallentin et al. NEJM 2009)
( Wallentin et al. NEJM 2009)
PLATO: Cumulative Incidence of the Time to
First Primary Outcome (Cardiovascular Death, Nonfatal Myocardial Infarction, or Stroke)
11.7%
9.8%
PLATO
Ticagrelor Cons
• Ticagrelor patients more
likely to discontinue
prematurely (23.4% vs. 21.5%,
p=0.002)
• Ticagrelor increased
dyspnea (13.8% vs. 7.8%
p<0.001)
• Ticagrelor increased non-
CABG-related bleeding
(4.5% vs. 3.8% p=0.03)
Ticagrelor Pros
• Benefit of Ticagrelor seen:
– Regardless of ACS
presentation
– Invasive vs. Noninvasive
management
• Reversible inhibition, can be
continued up until 24 hours
prior to CABG
• CV Mortality benefit seen
(4.5% vs. 5.9% p <0.001)
( Wallentin et al. NEJM 2009)
Platelet Inhibition 4 Hours After Loading
When Measured with LTA 20 μmol/L ADP
(Silvain J et al. Circ Cardiovasc Interv 2011)
A loading dose of a P2Y12 receptor inhibitor
should be given to patients undergoing PCI with
stenting. Options include:
• Clopidogrel 600 mg (ACS and non-ACS
patients).
• Prasugrel 60 mg (ACS patients).
• Ticagrelor 180 mg (ACS patients).
ACC/AHA Guideline for
DAPT Post-PCI
(Levine et al. JACC 2011)
I IIa IIb III
I IIa IIb III
In patients receiving a stent (BMS or DES)
during PCI for ACS, P2Y12 inhibitor therapy
should be given for at least 12 months.
Options include:
• clopidogrel 75 mg daily
• prasugrel 10 mg daily
• ticagrelor 90 mg twice daily.
(Levine et al. JACC 2011)
ACC/AHA Guideline for
DAPT Post-PCI
I IIa IIb III
I IIa IIb III
If the risk of morbidity from bleeding
outweighs the anticipated benefit afforded by
a recommended duration of P2Y12 inhibitor
therapy after stent implantation, earlier
discontinuation (e.g., <12 months) of P2Y12
inhibitor therapy is reasonable.
Continuation of DAPT beyond 12 months
may be considered in patients undergoing
DES implantation.
I IIa IIb III
ACC/AHA Guideline for
Duration of DAPT Post-PCI
(Levine et al. JACC 2011)
Cilostazol
• Phosphodiesterase III inhibitor
– Reversibly inhibits platelets
– Also promotes vasodilation and suppresses
intimal hyperplasia
• Reduced stent thrombosis and MI seen in
patients treated with ‘triple therapy’ in
3,099 patients undergoing DES
• ‘Triple therapy’ reduced angiographic
restenosis in diabetics undergoing DES
( Dixon et al. JACC 2009)
Glycoprotein IIb/IIIa Inhibitors
• Block the “final common pathway”
of platelet-thrombus formation
• Numerous trials show reduction of ischemic
events post-PCI in stable angina, ACS and
STEMI
– Overall, 35-50% reduction clinical events (ACCSAP-6 2005)
• Mortality benefit only seen in aggregate
data of 19 trials including 20,000 pts
Glycoprotein IIb/IIIa Antagonists
Abciximab Eptifibatide Tirofiban
Plasma t 1/2 10-30 min ~2.5 hours ~2 hours
Time to return
of platelet
function
24-48 hours 4-8 hours 4-8 hours
Excretion unknown ~50% renal 39-69% renal
Approved
Indications
PCI
Unstable angina
when PCI
planned within
24 hours
ACS and PCI ACS
Lincoff et al. JACC 2000
Abciximab
• Monoclonal antibody Fab fragments
– irreversible receptor inhibition
• Reversible effect with platelet transfusion
– Low drug to platelet ratio
• Used with ASA and heparin
• Risk of thrombocytopenia: monitor CBC
– Severe thrombocytopenia 1.0%
– Profound thrombocytopenia 0.4%
– Repeat dosing increases risk (~ 4%)
• Greatest in the first 30 days
• EPIC trial : pts high risk for events post PCI
– n~2,000 pts, 35% reduction events
• EPILOGUE: low risk PCI pts
– n~2,000, 50% reduction in events
• EPISTENT: PCI, also looked at PTCA vs. stenting
– n~2,400, ~50% reduction in events in stent pts
Abciximab PCI Trials
Abciximab STEMI Trials
• Two major STEMI trials
• CADILLAC (n~2,000)
– Also compared PTCA vs. stenting
– Event rate 20% PTCA alone 10% with
stent and abciximab
• ADMIRAL (n~300)
– Event rate 14.6% placebo 6.0% with
abciximab
– Higher infarct-artery patency with abciximab
pretreatent
Eptifibatide
• Short-acting small molecule, competative
inhibitor
• High molecule: receptor ratio
• Eliminated by kidney ~4 hrs after stopping
infusion
– Dose adjusted for renal dysfunction
• ESPRIT trial: PCI with stent (Lancet 2000)
– (n~2,000) ‘Double bolus’ resulted in reduced events
10.5% 6.6% (Death/MI/Urgent TVR/Bailout IIb/IIIa inhibitor)
– Increased Bleeding 1.3% vs. 0.4%, p=0.027)
Tirofiban
• Small molecule similar in biologic profile to
eptifibatide
• RESTORE trial: PCI in NSTEMI/UA
– n~2,100; risk reduction 38% at 48 hours
• TARGET trial: compared tirofiban to
abciximab in elective PCI (n~4,800)
– Abciximab superior as event rate 6.0% vs.
7.6% with tirofiban
Upstream GP IIb/IIIa Inhibitor in
NSTEMI/UA • PURSUIT showed benefit with pre-tx with
eptifibatide vs. placebo in NSTEMI/UA
– n~11,000; event rate 15.7% 14.2%,
greatest benefit in pts undergoing PCI
• GUSTO IV: NSTEMI/UA, medical tx only
– n~ 7,800; no benefit with abciximab if not
undergoing PCI
Other trials showed that delaying PCI for
prolonged pretreatment not beneficial
• In STEMI, early GP IIb/IIIa inhibitor use (ED
vs. cath lab) associated with increased
likelihood of TIMI 2-3 flow in a meta-analysis
of 6 trials (Montalescot et al. JAMA 2004)
• But, overall, not felt to be associated with a
clinical benefit
Upstream GP IIb/IIIa Inhibitor in
STEMI
I IIa IIb III
No Benefit
Routine precatheterization laboratory
administration of GP IIb/IIIa inhibitors as part of
an upstream strategy for patients with STEMI
undergoing PCI is not beneficial.
(Levine et al. JACC 2011)
Bleeding
• GP IIb/IIIa inhibitors shown to increase
bleeding compared to heparin or bivalirudin
alone
– Mostly access site-related
– Major bleeding < 2.0% if heparin dose is low
– Not shown to increase intracranial hemorrhage
– Contraindicated if recent stroke or prior
hemorrhagic stroke
I IIa IIb III
ACC/AHA Guideline for
GP IIb/IIIa Inhibitor During STEMI
(Levine et al. JACC 2011)
In patients undergoing primary PCI treated with UFH, it
is reasonable to administer a GP IIb/IIIa inhibitor
(abciximab, double-bolus eptifibatide, or high-bolus dose
tirofiban), whether or not pretreated with clopidogrel.
I IIa IIb III
For GP IIb/IIIa inhibitor administration in
patients not pretreated with clopidogrel.
For GP IIb/IIIa inhibitor administration
in patients who are pretreated with
clopidogrel.
In patients undergoing primary PCI
with abciximab, it may be reasonable to
administer intracoronary abciximab.
I IIa IIb III
ACC/AHA Guideline for
GP IIb/IIIa Inhibitor During STEMI
(Levine et al. JACC 2011)
In UA/NSTEMI patients with high-risk
features (e.g., elevated troponin level) not
treated with bivalirudin and not adequately
pretreated with clopidogrel, it is useful at the
time of PCI to administer a GP IIb/IIIa
inhibitor (abciximab, double-bolus
eptifibatide, or high-bolus dose tirofiban) in
patients treated with UFH.
Reasonable to use if pretreated with
clopidogrel
ACC/AHA Guideline for
GP IIb/IIIa Inhibitor in UA/NSTEMI
I IIa IIb III
(Levine et al. JACC 2011)
I IIa IIb III
ACC/AHA Guideline for
GP IIb/IIIa Inhibitor in ‘Elective’ PCI
• Limited benefit in stable, low risk elective PCI if
pretreated with clopidogrel
(Levine et al. JACC 2011)
In patients undergoing elective PCI treated
with UFH and not pretreated with
clopidogrel, it is reasonable to administer a
GP IIb/IIIa inhibitor (abciximab, double-
bolus eptifibatide, or high-bolus dose
tirofiban).
I IIa IIb III
PCI-Related Bleeding
and Mortality
(Doyle et al. JACC 2009)
Any major bleeding, as well as access-site bleeding, has
been associated with increased mortality, particularly if
blood transfusion required.
All patients should be evaluated for
risk of bleeding before PCI.
ACC/AHA Guideline on
Bleeding Risk
I IIa IIb III
(Levine et al. JACC 2011)
Summary/Conclusions
• The appropriate combination of
anticoagulation and antiplatelet therapy key
to minimizing ischemic as well as bleeding
complications.
• Always pretreat with ASA, and, unless
likely need for surgery, clopidogrel
• Newer P2Y12 antagonists result in more
reliable platelet inhibition with benefit in
ACS
• Heparin is inexpensive and reversible
• If patient pretreated with enoxaparin, do not
switch to heparin
• Consider bivalirudin if pretreated with
clopidogrel to decrease bleeding risk when
GP IIb/IIIa inhibitor not used
Summary/Conclusions
Summary/Conclusions
• Use GP IIb/IIIa inhibitor in high risk patients,
particularly if not pretreated with oral
antiplatelet therapy
• In ACS, early revascularization more
beneficial than prolonged pretreatment with
GP IIb/IIIa inhibitor
Summary/Conclusions
• And dose all medications appropriately for
weight and renal function