adjunctive pharmacology in the cardiac...

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


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


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


Incidence of Bleeding Events by

ACT Quartiles


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.


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


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


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)


• 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)


• 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


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


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


• 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


Bleeding at 28 Days

• No significant difference in major bleeding

• Trend towards minor bleeding if GpIIb/IIIa inhibitor use (p=0.08)


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




ACC/AHA Guideline for

Clopidogrel during PCI


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


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


Cumulative Kaplan-Meier Estimates of

Key Study End Points

Primary Efficacy End Point

Key Safety End Point


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:


Prasugrel should not be administered

in patients with a prior history of

stroke or TIA.

I IIa IIb III


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)


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)


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).


DAPT Post-PCI


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.



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


Duration of DAPT Post-PCI


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.


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


GP IIb/IIIa Inhibitor During STEMI


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


GP IIb/IIIa Inhibitor During STEMI


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


GP IIb/IIIa Inhibitor in UA/NSTEMI

I IIa IIb III


I IIa IIb III


GP IIb/IIIa Inhibitor in ‘Elective’ PCI

• Limited benefit in stable, low risk elective PCI if

pretreated with clopidogrel


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


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

adjunctive pharmacology in the cardiac...

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