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Optimal Adjunctive Medical

Therapy With PCI A Primer

Gregory W. Barsness, MD, FACC, FAHA, FSCAI

Consultant, Internal Medicine & Cardiology and Radiology Director, Mayo Clinic EECP Laboratory

Director, Cardiac Care Unit

Mayo Clinic College of Medicine

[email protected]

No Relationships to Disclose

2011 Mayo Clinic Symposium Bach Mai Hospital, Hanoi

The

Challenge

The Balance

Bleeding

Clotting

The Balance

Bleeding Clotting

The Balance

Age

Renal Failure

Bleeding Risk

Stable Angina (Elective PCI)

ACS (Urgent PCI)

The Balance

The Tools

Antiplatelet Agents

Aspirin

Thienopyridines: Clopidogrel, Ticlopidine

Glycoprotein IIb/IIIa Inhibitors

Others: Prasugrel, Ticagrelor, Cangrelor

Antithrombins

Unfractionated Heparin

Low Molecular Weight Heparins

Direct Antithrombins: Bivalirudin

Nat Rev 2003

Antiplatelet

agents

sites of action

Aspirin

Pharmacology

Prodrug, metabolized to salicylate

Absorption affected by food, antacid

buffer, enteric coating, chewing

Irreversible COX-1, COX-2 inhibition

Effect within minutes, peak in 1-2 hours

Aspirin

Beneficial in PTCA

77% reduction in ischemic complications Schwartz et al NEJM 1988

Dosing for PCI

On aspirin, then 75 to 325 mg before PCI

No aspirin, then 325 mg ≥2 hrs before PCI

Maintenance dose 162 mg

Low dose has similar efficacy but decreased bleeding then with higher doses

Clopidogrel Pharmacology

Absorption – not affected by food or antacids

Prodrug - converted by liver to active metabolite

Elimination half-life = 8 hours

Irreversible binding: biologic effects = platelet life

CREDO 28-Day Outcome Time to Effect of 300 mg Loading Dose

0

2

4

6

8

10

<6 Hours 6-24 Hours Overall

Death

/MI/

Urg

en

t R

evasc

Pretreatment

No Pretreatment

Steinhubl, TCT 2002

P=0.23

P=0.05

300 mg has insignificant effect

if < 6 hours before PCI

Clopidogrel Early Effect with 600 mg Oral Load

Circulation 2005;24:2560-4

20

30

40

50

60

<1 hr 2 to 4 hrs 4 to 6 hrs >6 hrs

5 mmol

ADP

platelet

aggreg

ation

(%)

Time from load

Clopidogrel load prior to PCI

2-12 hours 600 mg

>12 hours 300 mg

Newer P2Y12 Antagonists Pharmacology

Route Onset of action Platelet binding Biologic half-

life

Prasugrel PO Prodrug

peak = 2 hrs

irreversible 7-10 days

Cangrelor IV immediate reversible 3-6 min

Ticagrelor PO Not a prodrug

peak = 2 hrs

reversible 6 hrs

TRITON-TIMI 38 CV Death, MI, Stroke

0

5

10

15

0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450

Pri

mary

en

dp

oin

t (%

)

Days

Prasugrel

Clopidogrel

ITT = 13,608

Wiviott et al: NEJM 357:2001, 2007

HR 0.77 P=0.0001

HR 0.80 P=0.0003

12.1 (781)

HR 0.81 (0.73-0.90) P=0.0004 NNT=46

9.9 (643)

Less MI, but more bleeding!

Prasugrel is more potent than clopidogrel

Single 60 mg dose more effective than

single 300 mg dose clopidogrel

10 mg repeated dosing more effective

than 75 mg clopidogrel

Prasugrel

Alternative to clopidogrel at time of PCI

Caution in age >75 or weight <60 kg

Due to rapid onset and higher potency,

reasonable to wait until coronary anatomy

defined before loading

Discontinue 7 days prior to CABG

FDA Black Box Warning

Avoid use in patients with

prior stroke or TIA Absolute Contraindication

PLATO Trial CV Death, MI or Stroke

Days after randomisation

0 60 120 180 240 300 360

11 10

9 8 7 6 5 4 3 2 1 0

Cu

mu

lati

ve i

ncid

en

ce (

%)

9.8

11.7

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

Reduction in All Cause Mortality,

CV Mortality, MI, Stent Thrombosis

No Increase in Bleeding

12

Ticagrelor

Ventricular pauses ≥3 seconds in first week

Dyspnea

Creatinine (reversible)

FDA boxed warning

“…aspirin doses above 100 milligrams

per day decrease the effectiveness of

the medication.”

CP1279938-1

Medical therapy without stent

or PTCA alone

Bare-metal stent group

Drug-eluting stent group

ASA 75-162 mg/d indefinitely

+

Clopidogrel 75 mg/d for at least 1 mo

(class IA) and ideally up to

12 months

ASA 162-325 mg/d for at least 1 mo, then

75-162 mg/d indefinitely

+ Clopidogrel 75 mg/d or

Prasugrel 10 mg/d for 12 months.

Shorter duration if bleeding risk>benefit

ASA 162-325 mg/d for at least 3 mo for SES,

6 mo for PES, then 75-162 mg/d indefinitely

+ Clopidogrel 75 mg/d or

Prasugrel 10 mg/d for at least 12 months

Shorter duration if bleeding risk>benefit

Long-term Antiplatelet Therapy Acute and Stable Coronary Syndromes

Glycoprotein IIb/IIIa Inhibitors Pharmacology

Platelet

binding

Drug:

receptor

ratio

Dose

adjust

Plasma

half-life

Biologic

half-life

Abciximab Irreversible 1.5:1 Wt only 10-15

min

12-24 hrs

Epifibatide Reversible >>100:1 Wt + Crcl 2-2.5

hrs

=plasma

Tirofiban Reversible >>100:1 Wt + Crcl 2-2.5

hrs

=plasma

Drug Placebo RRR Trial IIb/IIIa (%) (%) (%)

EPIC Abciximab 8.3 12.8 35

EPILOG Abciximab 5.3 11.7 55

CAPTURE Abciximab 11.3 15.9 29

IMPACT-II Eptifibatide 9.5 11.4 17

RESTORE Tirofiban 8.0 10.5 24

EPISTENT Abciximab 5.3 10.8 51

ESPRIT Eptifibatide 6.8 10.5 35

Pooled 7.8 11.6 33

Composite endpoint

0.25 4 1

Odds ratio and 95% CIs

GP IIb/IIIa

better

Placebo

better

GP IIb/IIIa Inhibitors for PCI

Sabatine. Am J Med 2000;109:224-237

Studies done prior to routine clopidogrel

loading

Minimal benefit in low risk patients with

clopidogrel preload especially 600 mg > 2 hrs prior to PCI

Consider early GP IIb/IIIa inhibitor if no

clopidogrel preload

In ACS, no benefit to “upstream use”

unless no clopidogrel or prasugrel load

No need for prolonged infusion once

oral thienopyridine initiated

TF

Thrombin (IIa)

Prothrombin Endothelial cell

VIIa X Xa

UFH + AT

Fondaparinux + AT LMWH + AT

UFH + AT LMWH + AT

Bivalirudin

Hirudin

Thrombotic Cascade

The Tools

Antithrombin

Thrombin

Factor

Xa

Low-molecular

weight heparin

Pentasaccharide

sequence Factor

Xa

Antithrombin

Weitz: NEJM, 1997

Unfractioned

heparin

Pentasaccharide

sequence 13 unit

sequence

CM969878-26

Fondaparinux sodium (Synthetic pentasaccharide )

5 13 5

AT AT II X

UFH LMWH

5

Fondaparinux

X AT

Unfractionated Heparin Pharmacology

Discovered in cat brain tissue

Family of structurally-related

glycosaminoglycan compounds

MW 5-30,000 daltons (average 15k)

About 1/3 of molecules are active

Unfractionated Heparin Pharmacology

Narrow therapeutic window

Unpredictable dose-response curve

Heterogeneous mixture of active + inactive

Nonspecific binding to cells, plasma proteins

Inactivated by platelet factor 4

Requires and dependent on a cofactor (AT)

Rebound increase in thrombin generation

Intravenous administration required

Expensive monitoring required (aPTT)

UFH in PTCA Reducing Abrupt Closure

Narins, et al, Circulation 1996

UFH in PCI (and Stenting) Reducing Early Events

Chew, et al, Circulation 2001

Ischemic Events

Bleeding

Low Molecular Weight Heparins Pharmacology

Produced by depolymerization of UFH

Better bioavailability

Predictable dose-response curve

Ease of administration

Possibly improved safety profile

Coagulation monitoring unnecessary

Issues for PCI

Not readily reversible

Difficult to monitor

Direct Antithrombins Pharmacology

Direct reduction of thrombin activity

Inhibits clot-bound thrombin

Independent of AT

Examples

Hirudin, bivalirudin, lepirudin, argatroban,

efegatran, inogatran, melagatran

Bivalirudin Key Findings in ACUITY PCI

Bivalirudin Hep + GP IIb/IIIa

Composite ischemic 9% 8%

NNH = 100

Major bleeding 4% 8%

NNT = 25

Patients with no

clopidogrel preload

Composite ischemic 10% 7%

NNH = 33

Anticoagulant Choice Elective PCI

Class I recommendations

UFH (70-100 IU/kg IV bolus) or

Enoxaparin (0.75 mg/kg IV bolus) or

Bivalirudin if HIT

Class IIa recommendation

Bivalirudin in low-risk patients as alternative to UFH and GP IIb/IIIa inhibitor (0.5 mg/kg bolus with 1.75 mg/kg/hr drip)

Preload with clopidogrel

Anticoagulant Choice NSTEMI PCI

Very High Ischemic Risk

UFH + GP IIb/IIIa inhibitor (ACT 200-250s)

Bivalirudin (with clopidogrel load)

High Ischemic Risk

UFH (ACT 250-300s) ± GP IIb/IIIa inhibitor

Bivalirudin (including clopidogrel)

Enoxaparin

if <8 hours since last SC→no extra

if 8-12 hours, then 0.3 mg/kg IV

if >12 hours, then 0.75 mg/kg IV

Anticoagulant Choice Principles

Pretreatment with dual antiplatelet

therapy essential, regardless of

anticoagulant regiment

Avoid switching anticoagulants

(crossover) at the time of PCI,

especially between LMWH and UFH

If pre-PCI fondaparinux,

use UFH at time of PCI to

avoid catheter thrombosis