Why Heparin Still Has a Role in Contemporary PCI

James P. Zidar, MD, FACC, FSCAIAssociate Professor of MedicineDuke University Medical Center

Director, Cardiovascular ServicesDuke Raleigh Hospital

Conflicts / DisclosuresConsultant/Advisory Board member/ DSMB member/ research support:

-Abbott Vascular-Cordis-Medtronic-EV3

Off label use of products will not be discussed Off label use of products will not be discussed in this presentation. in this presentation.

Can we do better than heparin and aspirin?Can we do better than heparin and aspirin?

Sites of Anti-thrombotic Drug Action

Intrinsic, ExtrinsicPathways

Plasma clottingcascade

Prothrombin

Thrombin

Fibrinogen Fibrin

Thrombus

Platelet aggregation

Conformational activation of GPIIb/IIIa

Platelet Agonists

Thromboxane A2

ADP

AT III

FactorXa

Coagulationcascade

Coagulationcascade

PlateletcascadePlateletcascade

BivalirudinHirudin

ArgatrobanXimelagatran

UF HeparinFondaparinux

Thrombo-lytics

EnoxaparinDX-9065a

Aspirin

TiclopidineClopidogrel

GPIIb/IIIainhibitors

Unfractionated Heparin (UFH)• Referred to as standard or unfractionated heparin (UFH) and discovered in

1916 by a medical student, first clinical trials in 1938

• Named heparin because of its abundance in the liver, but found in highest amounts in highly vascularized tissues such as lung and intestine

• A catalytic cofactor for antithrombin III of 5,000 – 30,000 Daltons

• Heterogeneous mixture of polysaccharide chains with varying effects on anticoagulant activity

• Accelerates the action of circulating antithrombin (AT), a proteolytic enzyme which inactivates factors IIa (thrombin), IXa, Xa

• Prevents thrombus propagation, but does not lyse existing thrombi

UFHbound

toAT

Heparin’s Limitations

Heparin exhibitsa nonlinear dose-response

Heparin dose

AC

T

Fibrin

2

1

Thrombin2

1

Thrombin

2

1

ThrombinHeparin

Heparin cannot bind clot-bound thrombin P P

P

P

P

Heparin binds to plasma proteins and cells

PPCell

PPCell

PP

Heparin inactivated by Platelet Factor 4

Heparin activates platelets directly- GP IIb/IIIa activated- P-selectin expressed

+ Platelet ActivatedPlatelet

HeparinP-selectin

GP IIb/IIIa

Low concentrations of heparin increase the affinity of thrombin for fibrin.

Fibrin

ThrombinThrombin

ThrombinHeparin

+Thrombin

Heparin can induce and immune response such as HIT/TS and lead to thrombocytopenia and thrombosis

Anti-bodies

PlateletFactor 4+

Heparin

Historical Perspective on heparin monitoring

• In 1966, Hattersley describes the ACT

• In 1975, Bull et al recommended the use of ACTs to guide administration and reversal of heparin during cardiopulmonary bypass.

• ACT > 300 sec: No clots in the extracorporeal circuit

• In 1977, Verska reported on the use of a new automated ACT machine to guide heparin therapy.

• ACT gains widespread use to monitor heparin Rx• ACT quick, easy, and reliable Standard of care

• aPTTs non-linear, unreliable response at higher heparin doses

Bull BS, et al Thorac Cardiovasc Surg. 1975 May;69(5):674–684Verska JJ. Ann Thorac Surg. 1977 Aug;24(2):170–173.

Anticoagulation in POBARetrospective Analyses - ACT and OutcomeRetrospective Analyses - ACT and Outcome

Ferguson et al. JACC 1994;23:1061Ferguson et al. JACC 1994;23:1061

<250<250 250 - 275250 - 275 275 - 300275 - 300 >300>30000

2020

4040

6060

8080% of Patients% of Patients

ACT (sec)ACT (sec)

61.261.2

27.027.020.420.4

17.017.010.710.7

35.035.0

7.77.7

21.021.0

+ Complication

- Complication

Narins CR, et al. Circulation 1996:93;667–671Narins CR, et al. Circulation 1996:93;667–671

0.10

0.20

0.0350 450

0.05

Prob. of Abrupt Closure

550250

0.15

Initial ACT (sec) Hemochron Monitoring Device

0.10

0.20

0.0350 450

0.05

Prob. of Abrupt Closure

550250

0.15

Initial ACT (sec) Hemochron Monitoring Device

n = 1290n = 1290

“no safe threshold”

“inverse relation betweenintensity of ACT and riskof abrupt closure”

“no safe threshold”“no safe threshold”

“inverse relation between“inverse relation betweenintensity of ACT and riskintensity of ACT and riskof abrupt closure”of abrupt closure”

Narins et al. Circ 1996;93:667Narins et al. Circ 1996;93:667

Unfractionated HeparinOptimal Efficacy vs Optimal Safety*

02468

1012141618

0-

275

276-

300

301-

325

326-

350

351-

375

376-

400

401-

425

426-

475

476-

525

526-

Probability of

ischemic

event/hemorrhage

ACT (sec)

Best for lowbleeding

Best for lowischemia

Hemorrhage vs maximum ACT during procedure Ischemic events vs minimum ACT at device activation

* ACT vs adverse outcomes in pts treated with UFH - meta-analysis of recent major trials of PCI

Chew et al, Circulation 2001;103:961

Heparin During PCI:Overview of 6 RCTs

Chew DP. Circulation 2001;103:961Chew DP. Circulation 2001;103:961

00

33

66

99

1212

200200 250250 300300 350350 400400 450450

Death, MI, or Revasc (7 Days) - %Death, MI, or Revasc (7 Days) - %

ACT at Device Activation (s)ACT at Device Activation (s)

10.110.111.111.1

8.68.6 8.98.9

6.66.67.57.5 7.77.7

9.89.8

00

33

66

99

1212

1515

1818

200200 250250 300300 350350 400400 450450

Major Bleeding - %Major Bleeding - %

Maximum ACT (s)Maximum ACT (s)

16.916.9

12.412.4

8.68.69.99.9

12.412.413.713.7

12.412.4

16.316.3N = 5216

ACT and Clinical Outcome among pts on UFH alone: Best target 350-375 s?

ACT and Clinical Outcome among pts on UFH alone: Best target 350-375 s?

n=5,216; 1992-1998

Heparin During PCI:Overview of 6 RCTs

GP IIb/IIIa blunt events with lower ACTDeath, MI, RevascDeath, MI, Revasc

HeparinHeparin Abcix and HeparinAbcix and Heparin

Chew DP. Circulation 2001;103:961Chew DP. Circulation 2001;103:961

Overview of 4 PCI Overview of 4 PCI TrialsTrials

• History of 7 trials over 10yrs

• Both thrombotic and bleeding complications have decreased

• ACTs have decreased

• No difference in ACT between pts with (dark) and without (lighter) events

• History of 7 trials over 10yrs

• Both thrombotic and bleeding complications have decreased

• ACTs have decreased

• No difference in ACT between pts with (dark) and without (lighter) events

Death, M

I, TV

RD

eath, MI, T

VR

Major +

Minor B

leedM

ajor + M

inor Bleed

event rate

event rate

Brener SJ. Circulation 2004;110:994-998

Overview of 4 PCI TrialsUniversal Stenting & Aggressive Platelet Inhibition

Death, MI, TVRDeath, MI, TVR Major + Minor BleedMajor + Minor Bleed

48 hr Outcomes According to Max ACT (Covariate Adj.) No interaction with ACS, diabetes

Brener SJ. Circulation 2004;110:994-998

100 200 300 400 500 600 700Maximum ACT (Sec)Maximum ACT (Sec)

0.10

0.08

0.06

0.04

0.02

0.00 100 200 300 400 500 600 700Maximum ACT (Sec)

0.05

0.04

0.03

0.02

0.01

0.00

n=9974, 1999-2002

ISAR-REACT Trial

• Acute coronary syndrome • Acute MI <14 days• ST segment depression• Positive biomarkers• Insulin dependent diabetes

• Chronic total coclusions • EF < 30%• Thrombus present• Lesions in bypass grafts

2159 low-risk patients having elective PCIExclusions:

Clopidogrel (600 mg load dose, 2 x 75 mg/day through discharge, 75 mg/day for 4 wks)

Abciximab n=1079

Placebo n=1080

Endpoints:Primary : 30 day Death / MI / Urgent TVRSecondary: 30 day bleeding complications

Kastrati: NEJM 2004; 350:232

4.2

0.3 0.4

3.3

0.9

4

0.30.5

3.3

0.7

0

2

4

D/MI/TVR Death Q-MI Non-q-MI TVR

Even

ts%

Abciximab (n=1079)

Placebo (n=1080)

4.2

0.3 0.4

3.3

0.9

4

0.30.5

3.3

0.7

0

2

4

D/MI/TVR Death Q-MI Non-q-MI TVR

Even

ts%

Abciximab (n=1079)

Placebo (n=1080)

—Kastrati A, et al. NEJM 350;2004—Kastrati A, et al. NEJM 350;2004

ISAR-REACT: Results to 30 Days

• 2159 stent pts• No ACS/MI

• No IDDM

• Clopidogrel• 600 mg > 2hrs pre-

PCI

• 75 mg bid until discharge

• 75 mg qd (mo)

• Abciximab or placebo

• UFH

• 2159 stent pts• No ACS/MI

• No IDDM

• Clopidogrel• 600 mg > 2hrs pre-

PCI

• 75 mg bid until discharge

• 75 mg qd (mo)

• Abciximab or placebo

• UFH

1.10.7

0

1

2

3

4

1.10.7

0

1

2

3

4

2.5

1.9

0

1

2

3

4

2.5

1.9

0

1

2

3

4

2.4

0.9

0

1

2

3

4

2.4

0.9

0

1

2

3

4

Abciximab Abciximab AbciximabPlacebo Placebo Placebo

TIMI Major Bleed TIMI Minor Bleed Transfusion

p=0.82

p<0.05p=NS

ISAR-REACT: BleedingISAR-REACT: Bleeding

%

30 day Events

Kastrati: NEJM 2004; 350:232

ISAR-REACT 2: Outcomes and Troponin StatusAbciximab + Clopidogrel in ACS Undergoing PCI

4.6% 4.6%

%

5%

10%

15%

20%

Abciximab Placebo

Troponin negative ( <0.03µg/L, n=973)Troponin negative ( <0.03µg/L, n=973)

p=0.98

Pri

mar

y E

ven

tsP

rim

ary

Ev

ents 13.1%

18.3%

%

5%

10%

15%

20%

Abciximab Placebo

Troponin positive (>0.03 µg/L, n=1049)Troponin positive

(>0.03 µg/L, n=1049)

p=0.02

Kastrati A, Mehilli J , et al. JAMA. 2006 Apr 5;295(13):1531-8.Kastrati A, Mehilli J , et al. JAMA. 2006 Apr 5;295(13):1531-8.

Heparin 140 u/kgHeparin 140 u/kg

Similar to ISAR-REACT 1

REPLACE-2 Trial DesignBivalirudin vs Heparin + GP IIb/IIIa During PCIBivalirudin vs Heparin + GP IIb/IIIa During PCI

Randomization - double blind, triple dummyRandomization - double blind, triple dummyN = 6010 Patients: Urgent or Elective PCI N = 6010 Patients: Urgent or Elective PCI

Heparin65 U/kg initial bolus

Planned GP IIb/IIIa(abciximab or eptifibatide)

Heparin65 U/kg initial bolus

Planned GP IIb/IIIa(abciximab or eptifibatide)

Bivalirudin0.75 mg/kg initial bolus,

1.75 mg/kg-hr during PCI

Provisional GP IIb/IIIa(abciximab or eptifibatide)

Bivalirudin0.75 mg/kg initial bolus,

1.75 mg/kg-hr during PCI

Provisional GP IIb/IIIa(abciximab or eptifibatide)

abciximab: 0.25 mg/kg bolus, 0.125 g/kg-min (max 10 g/min) x 12 hrs

eptifibatide: 180 g/kg double bolus, 2.0 g/kg-min x 18-24 hrs

““Quadruple Endpoint” at 30 DaysQuadruple Endpoint” at 30 Days ““Quadruple Endpoint” at 30 DaysQuadruple Endpoint” at 30 Days

target ACTtarget ACT>> 225 sec 225 sec

Quadruple Endpoint 30 Day Primary Endpoint Components30 Day Primary Endpoint Components

CompositeComposite DeathDeath MIMI Urgent RevascUrgent Revasc

Major Bleeding

Major Bleeding

00

22

44

66

88

1010

1212% of Patients% of Patients

10.010.09.29.2

0.40.4 0.20.2

6.26.27.07.0

1.41.4 1.21.2

4.14.1

2.42.4

Heparin + GP IIb/IIIa (n = 3008)

Bivalirudin (n = 2994)

p <0.001

Triple Ischemic Endpoint

Heparin+GP IIb/IIIa(n=3008)

Heparin+GP IIb/IIIa(n=3008)

Bivalirudin

(n=2994)

Bivalirudin

(n=2994)

00

22

44

66

88

1010Death, MI, Urg Rev (%)Death, MI, Urg Rev (%)

7.17.17.67.6

Odds Ratio = 1.088(0.895 - 1.322)

p = 0.40

HeparinHeparinsuperioritysuperiorityboundaryboundary

•Triple ischemic endpoint actually favored the haparin = GP2b3a group

Do we need any anti-thrombin in elective PCI?Do we need any anti-thrombin in elective PCI?

• Prospective, consecutive 500 pt registry with abciximab and minimal dose UFH (< 1000 U)*• Median ACT 168 sec• Non Q MI 1.6%• Major bleeding 0.2%, minor bleeding 3.6%• Thrombocytopenia 2.2%• 30 day events 0.2%

*Denardo, AJC 2003; 91: 1-5.*Denardo, AJC 2003; 91: 1-5.

Ciao Study: PCI without Heparin?

Stabile E. et al, JACC 2008;52:1293-8

0

3.1

0.6

3.7

1.1

0

2

0.3

2

0.6

0

1

2

3

4

Death MI UrgTVR

MACE TIMIBleeds

% o

f P

ati

en

ts

Heparin

No HeparinAll p values=NS

700 chronic CAD patients with low-risk lesions enrolled between 6/06 – 1/07

ASA 75-160 mg/dayClopidogrel 75 mg for 7d or 300 mg 24 h prior

GPI at operator’s discretion

PlaceboHeparin 70-100 U/KgTarget ACT<250 sec

Sheath Removed in Holding AreaIndependent of ACT

30-day F/UDeath/MI/urgent TVR

RR

ACT=201±34 sec ACT=125±25 sec

PCI/Stent (5F System)

Protamine • Can reverse effects of heparin

• Test dose – 10 mg, wait 10 minutes give 10-30 mg to reduce ACT as required.

• Adverse affects- incidence 0.06-10.6%• catastrophic events - rare

• major adverse responses occur during 2.6% of cardiac surgical procedures

• “Risk factors” in 39% of CABG surgery patients, including:• fish allergy or previous exposure to protamine

• diabetics treated with protamine zinc insulin

• previous drug reaction

• Hemodynamic changes• transient systemic hypotension and pulmonary hypertension observed

• complement activation and inflammatory mediators

• Drug reactions• related to rapid drug administration

Lack of Impact of Randomized Trials on Percutaneous Coronary Intervention Practice: Data fromthe National Cardiovascular Data Registry

Sunil V. Rao MD, Dadi Dai MS, Sameer K. Mehta MD, Steven Marso MD, Eric D. Sunil V. Rao MD, Dadi Dai MS, Sameer K. Mehta MD, Steven Marso MD, Eric D.

Peterson MD MPH, Timothy Sanborn MD, Lloyd W. Klein MD on behalf of the NCDRPeterson MD MPH, Timothy Sanborn MD, Lloyd W. Klein MD on behalf of the NCDR

NCDR CathPCICurrent Antithrombotic Strategies

NCDR CathPCICurrent Antithrombotic Strategies

Q2 2007 – Q1 2008

• Unfractionated Heparin 53%

• Thrombin Inhibitors (any) 43%

• LMWH (any) 15%

• GP IIbIIIa inhibitors (any) 39%

Cost comparison of anti-coagulant approaches

Abx/hep Eftifib/hep Bival Hep/clopDose 12h 18h 2h 1 hr

Bolus? yes yes Yes Yes

Infusion yes yes ? No

Vial $747 $120(2) $691 $3Infusion costs 747 376 -

HospitalCosts (US$) $1490 $616 $616-1232 $3

Duke Raleigh Hospital Pharmacy costs: 2009Duke Raleigh Hospital Pharmacy costs: 2009Duke Raleigh Hospital Pharmacy costs: 2009Duke Raleigh Hospital Pharmacy costs: 2009

Unfractionated Heparin and ACT

Heparin + GPI:• Dose

• Bolus 50-70 u/kg

• Additional 2000-5000u

• ACT Target• HemoTec >200s

• Hemochron >200s

Heparin Monotherapy:

• Dose• Bolus 70-100 u/kg

• Additional 2000-5000u

• ACT Target• HemoTec 250-300s

• Hemochron 300-350s

ACC/AHA 2005 PCI Guidelines.

Hemochron usually exceeds HemoTec by 30-50s (variable)

• Varies substantially after fixed dose heparin

• Weight-adjusted dose generally preferred

• Controversy regarding ACT and ischemic/bleeding complications

Heparin Dosing(Zidar algorithm)

• Dose varies for applications

• Bolus 40-75u/kg and monitor ACT q30 minutes

Pts pretreated with clopidogrel

• Elective case without 2b3a – ACT >250.

• Elective case with 2b3a - ACT >200

• Acute case without 2b3a – ACT>300

• Acute case with 2b3a – ACT > 250.

Conclusions• Heparin is safe and effective with very low event

rates in contemporary practice, especially stable elective patients who are pretreated with clopidogrel

• Positive and linear bleeding response with increasing levels of anticoagulation

• Heparin is easily reversible with protamine

• It is clearly the cheapest strategy in the cath lab

• Heparin remains the most popular choice in US labs