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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
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