Transcript 0830_Zidar SCAI heparin final talk

Why Heparin Still Has a Role in
Contemporary PCI
James P. Zidar, MD, FACC, FSCAI
Associate Professor of Medicine
Duke University Medical Center
Director, Cardiovascular Services
Duke Raleigh Hospital
Conflicts / Disclosures
Consultant/Advisory Board member/
DSMB member/ research support:
-Abbott Vascular
-Cordis
-Medtronic
-EV3
Off label use of products will not be discussed
in this presentation.
Can we do better than heparin and aspirin?
Sites of Anti-thrombotic Drug Action
Intrinsic, Extrinsic
Pathways
Coagulation
cascade
Platelet Agonists
Aspirin
Plasma clotting
cascade
ADP
Thromboxane A2
Enoxaparin
DX-9065a
UF Heparin
Fondaparinux
Prothrombin
Factor
Xa
Ticlopidine
Clopidogrel
Conformational
activation of GPIIb/IIIa
GPIIb/IIIa
inhibitors
AT III
Thrombin
Bivalirudin
Hirudin
Argatroban
Ximelagatran
Platelet
cascade
Platelet aggregation
Fibrinogen
Thrombolytics
Fibrin
Thrombus
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
UFH
bound
to
AT
Heparin’s Limitations
Heparin
Heparin activates
platelets directly
+
- GP IIb/IIIa activated
- P-selectin expressed
Low concentrations of
heparin increase the
affinity of thrombin for
fibrin.
Platelet
Activated
Platelet
Heparin
+
P-selectin
GP IIb/IIIa
Thrombin
Thrombin
Thrombin
Thrombin
Heparin inactivated by
Platelet Factor 4
Fibrin
2
Thrombin
Heparin
Heparin cannot
bind clot-bound
thrombin
P
Thrombin
P
P
1
2
2
Thrombin
1
P
P
1
Fibrin
Heparin binds to
plasma proteins and
cells
Heparin
+
Platelet
Factor 4
Antibodies
ACT
Heparin can induce
and immune response
such as HIT/TS and
lead to
thrombocytopenia and
thrombosis
Heparin exhibits
a nonlinear doseresponse
PP
Cell
PP
Cell
Heparin dose
PP
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):674–684
Verska JJ. Ann Thorac Surg. 1977 Aug;24(2):170–173.
Anticoagulation in POBA
Retrospective Analyses - ACT and Outcome
0.20
Prob. of Abrupt Closure
n = 1290

0.15

0.10
0.05
N
0.0
250
350
450
Initial ACT (sec)
Hemochron Monitoring Device
Ferguson et al. JACC 1994;23:1061
Narins et al. Circ 1996;93:667
550
Unfractionated Heparin
Optimal Efficacy vs Optimal Safety*
* ACT vs adverse outcomes in pts treated with UFH - meta-analysis of recent major trials of PCI
Hemorrhage vs maximum ACT during procedure
18
16
14
12
10
8
6
4
2
0
Best for low
bleeding
Ischemic events vs minimum ACT at device activation
Best for low
ischemia
0276- 301- 326- 351- 376- 401- 426- 476- 526275 300 325 350 375 400 425 475 525
ACT (sec)
Chew et al, Circulation 2001;103:961
Heparin During PCI:
Overview of 6 RCTs
ACT and Clinical Outcome among pts on UFH alone:
Best target 350-375 s?
N = 5216
11.1
10.1
16.9
16.3
9.8
8.6 8.9
7.5 7.7
6.6
13.7
12.4
12.4
12.4
9.9
8.6
n=5,216; 1992-1998
Chew DP. Circulation 2001;103:961
Heparin During PCI:
Overview of 6 RCTs
GP IIb/IIIa blunt events with lower ACT
Death, MI, Revasc
Heparin
Abcix and Heparin
Chew DP. Circulation 2001;103:961
• History of 7 trials over 10yrs
• Both thrombotic and bleeding
complications have decreased
pts with (dark) and without
(lighter) events
Brener SJ. Circulation 2004;110:994-998
event rate
Major + Minor Bleed
• ACTs have decreased
• No difference in ACT between
Death, MI, TVR
Overview of 4 PCI
Trials
event rate
Overview of 4 PCI Trials
Universal Stenting & Aggressive Platelet Inhibition
48 hr Outcomes According to Max ACT (Covariate Adj.)
No interaction with ACS, diabetes
0.10
0.05
0.08
0.04
0.06
0.03
0.04
0.02
0.02
0.01
0.00
100
200
300
400
500
600
Maximum ACT (Sec)
700
Death, MI, TVR
0.00
100
200
300
400
500
600
Maximum ACT (Sec)
700
Major + Minor Bleed
n=9974, 1999-2002
Brener SJ. Circulation 2004;110:994-998
ISAR-REACT Trial
2159 low-risk patients having elective PCI
Exclusions:
•
•
•
•
•
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
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 TVR
Secondary: 30 day bleeding complications
Kastrati: NEJM 2004; 350:232
ISAR-REACT: Results to 30 Days
4.2
• 2159 stent pts
Abciximab (n=1079)
4
4
Placebo (n=1080)
Events%
3.3 3.3
•
PCI
• 75 mg bid until
discharge
• 75 mg qd (mo)
2
0.9
0.3 0.3
0.4 0.5
0.7
0
D/MI/TVR
Death
Q-MI
Non-q-MI
TVR
• No ACS/MI
• No IDDM
Clopidogrel
• 600 mg > 2hrs pre-
• Abciximab or
•
placebo
UFH
—Kastrati A, et al. NEJM 350;2004
ISAR-REACT: Bleeding
30 day Events
%
TIMI Major Bleed
4
TIMI Minor Bleed
4
Transfusion
4
p<0.05
p=NS
3
3
2.5
p=0.82
2
1
3
1.9
2
1.1
0.7
0
Abciximab
Placebo
2.4
2
1
1
0
0
Abciximab
Placebo
0.9
Abciximab
Placebo
Kastrati: NEJM 2004; 350:232
ISAR-REACT 2: Outcomes and Troponin Status
Abciximab + Clopidogrel in ACS Undergoing PCI
Troponin positive
(>0.03 µg/L, n=1049)
20%
p=0.02
Primary Events
15%
18.3%
Troponin negative
( <0.03µg/L, n=973)
20%
p=0.98
15%
13.1%
10%
10%
5%
5%
%
%
Abciximab
Placebo
Heparin 140 u/kg
Similar to ISAR-REACT 1
4.6%
4.6%
Abciximab
Placebo
Heparin 140 u/kg
Kastrati A, Mehilli J , et al. JAMA. 2006 Apr 5;295(13):1531-8.
REPLACE-2 Trial Design
Bivalirudin vs Heparin + GP IIb/IIIa During PCI
N = 6010 Patients: Urgent or Elective PCI
Randomization - double blind, triple dummy
Heparin
65 U/kg initial bolus
Planned GP IIb/IIIa
(abciximab or eptifibatide)
target ACT
> 225 sec
Bivalirudin
0.75 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 mg/kg-min (max 10 mg/min) x 12 hrs
eptifibatide: 180 mg/kg double bolus, 2.0 mg/kg-min x 18-24 hrs
 “Quadruple Endpoint” at 30 Days 
Quadruple Endpoint
30 Day Primary Endpoint Components
p <0.001
Triple Ischemic Endpoint
•Triple ischemic endpoint
actually favored the
haparin = GP2b3a group
Odds Ratio = 1.088
(0.895 - 1.322)
p = 0.40
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.
Ciao Study: PCI without Heparin?
700 chronic CAD patients with low-risk
lesions enrolled between 6/06 – 1/07
ASA 75-160 mg/day
Clopidogrel 75 mg for 7d or 300 mg 24 h prior
GPI at operator’s discretion
Heparin
All p values=NS
No Heparin
R
3.7
4
Placebo
ACT=201±34
sec
ACT=125±25
sec
PCI/Stent (5F System)
3.1
% of Patients
Heparin 70-100 U/Kg
Target ACT<250 sec
3
2
2
2
1.1
1
0.6
0.6
0.3
0 0
Sheath Removed in Holding Area
Independent of ACT
30-day F/U
Death/MI/urgent TVR
0
Death
MI
Urg
TVR
MACE
TIMI
Bleeds
Stabile E. et al, JACC 2008;52:1293-8
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 from
the National Cardiovascular Data Registry
NCDR CathPCI
Current 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/clop
Dose
Bolus?
Infusion
12h
yes
yes
18h
yes
yes
2h
Yes
?
1 hr
Yes
No
Vial
$120(2)
376
$691
-
$3
Infusion costs
$747
747
Hospital
Costs (US$)
$1490
$616
$616-1232
$3
Duke Raleigh Hospital Pharmacy costs: 2009
Unfractionated Heparin and ACT
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 Monotherapy:
Dose
• Bolus 70-100 u/kg
• Additional 2000-5000u
ACT Target
• HemoTec 250-300s
• Hemochron 300-350s
Heparin + GPI:
• Dose
•
• Bolus 50-70 u/kg
• Additional 2000-5000u
ACT Target
• HemoTec >200s
• Hemochron >200s
ACC/AHA 2005 PCI Guidelines.
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