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Interventional Pharmacology:The Basics
Interventional Pharmacology:The Basics
Michael J. Cowley, FACC,FSCAIMichael J. Cowley, FACC,FSCAI
Nothing to Disclose
• Heparin (UFH)
• GP IIb/IIIa Receptor Antagonists
• Low Molecular Weight Heparins
• Direct Thrombin Inhibitors
• Thienopyridines
• Heparin (UFH)
• GP IIb/IIIa Receptor Antagonists
• Low Molecular Weight Heparins
• Direct Thrombin Inhibitors
• Thienopyridines
Interventional Pharmacology
Adjunctive Therapy for ACS / PCIAdjunctive Therapy for ACS / PCI
GP 2b3a Agents
Abciximab
Eptifibatide
Tirofiban
+ Clopidogrel pre-treatment how early? how much?
Anti Thrombins
Heparin
LMWH
Bivalirudin
UFH: Clinical Experience, Non-inferiority
GP2b3a: Numerous studies (vs UFH alone) LMWH: ESSENCE, TIMI 11, INTERACT SYNERGY, STEEPLE
Clopdiogrel: CURE, PCI-CURE, CREDO
Bivalirudin: BAT, REPLACE 2, ACUITY
Beneficial AgentsInterventional Pharmacology
Interventional PharmacologyInterventional Pharmacology
Anti-Thrombin Effects
Platelet Effects
UFH Xa / IIa Aggregation
GP 2b/3a --- Inhibition
ADP inhibitor --- Inhibition
LMWH Xa / IIa Minimal effect
Bivalirudin IIa (direct) Inhibition
Unfractionated Heparin
Unfractionated Heparin
Unfractionated HeparinUnfractionated Heparin
Indirect thrombin inhibitor (does not inhibit clot-bound thrombin)
Nonspecific binding to:― Plasma proteins ― Endothelial cells
(variable anticoagulation level)
Inhibited by platelet factor 4 ― reduced effect in ACS
Causes platelet aggregation
Risk of HIT
Disadvantages Multiple sites of action in
coagulation cascade (IIa,Xa)
Long history of successful clinical use
Readily monitored by aPTT and ACT
Very inexpensive
Advantages
Hirsh J, et al. Circulation. 2001;103:2994-3018
ACC/AHA/SCAI PCI GuidelinesACC/AHA/SCAI PCI Guidelines
• UFH should be given to pts under-going PCI (Level of Evidence: C)
• UFH should be given to pts under-going PCI (Level of Evidence: C)
Unfractionated Heparin
Class I:
GP IIb / IIIa Receptor Antagonists
GP IIb / IIIa Receptor Antagonists
GP IIb/IIIa Receptor InhibitionGP IIb/IIIa Receptor Inhibition
EPIC CAPTURE SPEED RAPPORTEPILOG PRISM TIMI 14 ADMIRAL RESTORE PRISM PLUS GUSTO 5 ISAR 2IMPACT PURSUIT ASSENT 3 CADILLACIMPACT 2 GUSTO 4 Impact AMI ACE EPISTENTESPRIT TARGET
STEMI PCI ACS Lysis PCI
GPIIb/IIIa Antagonists in PCI
Risk Ratio & 95% CIRisk Ratio & 95% CI
EPICEPIC
IMPACT-IIIMPACT-II
EPILOGEPILOG
CAPTURECAPTURE
Trial
9.6%9.6%
8.5%8.5%
9.1%9.1%
9.0%9.0%
6.3%6.3%RESTORERESTORE
Placebo IIb/IIIa
6.6%6.6%
7.0%7.0%
4.0%4.0%
4.8%4.8%
5.1%5.1%
2,0992,099
4,0104,010
2,7922,792
1,2651,265
2,1412,141
N
10.2%10.2%EPISTENTEPISTENT 5.2%5.2%2,3992,399
Placebo Better
IIb/IIIa Antag Better
0.62 (0.55, 0.71)p < 0.000000001 8.8%8.8%Pooled 5.6%5.6%16,770
0 0.5 1 1.5 2
ESPRITESPRIT 2,0642,064 10.2%10.2% 6.3%6.3%
30 Day Death / MI
20.1
9.1
19.5
6.5
17.6
7.1
15.8
9.2
15.5
8.6
13.6
7.3
13
5.8
13
6.5
12.2
6.7
0
10
20
30
Bifurc Calcif Angl>45 Tort Ostial Thromb Ecc Irreg LL>10
Placebo Abciximab
20.1
9.1
19.5
6.5
17.6
7.1
15.8
9.2
15.5
8.6
13.6
7.3
13
5.8
13
6.5
12.2
6.7
0
10
20
30
Bifurc Calcif Angl>45 Tort Ostial Thromb Ecc Irreg LL>10
Placebo Abciximab
%
p=.047
30 day Events (D, MI, uTVR): EPIC and EPILOG
Abciximab in PCI: Complex Lesions
p=.001 p=.001
p=.001
p=.001 p=.078
p=.001 p=.001 p=.001
Ellis: JACC 1998; 32:1619
365 452 761 961 380 799 2994 2312 1896
74.1
12.5
5.6
0
10
20
Type A / B1 Type B2 / C
Placebo Abciximab
74.1
12.5
5.6
0
10
20
Type A / B1 Type B2 / C
Placebo Abciximab
%
Abciximab for Complex Lesions: EPISTENT
30 day D, MI, uTVR
p=0.17 p<0.001
230 267 517 468
12
4.6
10.5
5
14.7
7.3 74.6
10.5
4.5
0
10
20
30
Rapport ISAR 2 Admiral Cadillac ACE
No Abciximab
Abciximab
12
4.6
10.5
5
14.7
7.3 74.6
10.5
4.5
0
10
20
30
Rapport ISAR 2 Admiral Cadillac ACE
No Abciximab
Abciximab
%
GP IIb/IIIa in Acute MIAbciximab PCI in Acute MI TrialsAbciximab PCI in Acute MI Trials30 Day Endpoint (D, Re-MI, Urg TVR)30 Day Endpoint (D, Re-MI, Urg TVR)
p=0.023
p<0.05p=0.005
PTCAPTCAN = 483N = 483
StentStentN = 401N = 401
StentStentN = 301N = 301
PTCA or StentPTCA or StentN = 2082N = 2082
StentStentN = 400N = 400
p=0.038
p=0.01
Anti-Platelet TherapyAnti-Platelet Therapy
10.1
5.0*
Placebo158
ASA178
0
4
8
12
Pat
ien
ts (
%)
11.9
3.3*
Placebo118
ASA121
0
5
10
1512.9
6.2*
Placebo279
ASA276
0
5
10
15
Lewis HD Jr: NEJM 1983309:396-403
Theroux P: NEJM 1988
319:1105-1111
Cairns JA: NEJM 1985
313:1369-1375
17.1
6.5*
Placebo397
ASA399
0
5
10
15
20
The RISC Group: Lancet 1990336:827-830
Death or MI
*p = .0005 *p = .012 *p = .008 * p<.0001
ASA in UA/NSTEMIASA in UA/NSTEMI
CURE Primary End Point: MI/Stroke/CV Death
CURE Primary End Point: MI/Stroke/CV Death
Months of Follow-up
Clopidogrel + Aspirin *(n=6259)
Placebo + Aspirin *(n=6303)
p < 0.001N=12,562
3 6 90 12
20%Relative RiskReduction
0.12
0.14
0.10
0.06
0.08
0.00
0.04
0.02
Cu
mu
lati
ve H
aza
rd R
ate
* In addition to other standard therapies
Yusuf S: N Engl J Med 2001;345:494-502
Clopidogrel
100100 200200 300300
Placebo
p = 0.002p = 0.002
Days of Follow-UpDays of Follow-Up
CURE PCI Substudy CURE PCI Substudy
00 400400
PCI-
31% RRR
The CURE Investigators: Lancet August 2001
N = 2,658
0.00
0.02
0.04
0.06
0.08
0.10
Cu
mu
lati
ve H
azar
d R
ate
s
Months
0 3 6 9 12
8.5%
11.5%
0
5
15
10
ClopidogrelN=1053
PlaceboN=1063
Death, MI or Stroke
27% RRR p = 0.02
CREDO: 1 Year Primary OutcomeCREDO: 1 Year Primary Outcome
%
Circulation 2005; 112:2946-2950
ISAR-CHOICE
Circles represent single measurements; bars denote mean ± SD
von Beckerath N, et al: Circulation 2005;112:2946-2950
120
100
80
60
40
20
0300 mg 600 mg 900 mg
n = 20 n = 20 n = 20
p = .01 p = .59
p = 0.001A
AD
P (
5 µ
mo
l/L
)-In
du
ced
Ag
gre
gat
ion
(%
)
120
100
80
60
40
20
0300 mg 600 mg 900 mg
n = 20 n = 20 n = 20
p = 0.01 p = .59
p = 0.001B
AD
P (
20 µ
mo
l/L
)-In
du
ced
Ag
gre
gat
ion
(%
) 5 µmol/L ADP 20 µmol/L ADP
Platelet Aggregation 4h after Clopidogrel Loading
ARMYDA-2 TrialARMYDA-2 TrialPrimary Endpoint: death, MI,
or TVR at 30 days
4%
0%
2%
4%
6%
8%
10%
12%
14%
High Dose Standard Dose
12%
Clopidogrel Loading Dose
600 mgPre-PCI
Clopidogrel Loading Dose
300 mgPre-PCI
255 patients with stable CAD or NSTEMI prior to PCI
13% GP IIb/IIIa inhibitors20% DES
Randomized 4-8 hrs Pre-PCI
p=0.041
Patti G et al:. Circulation 2005;111:2099-2106
0.4 0.6 0.8 1.0 1.2
Hazard Ratio (95% CI)
RRR: –13.4%p=0.60
RRR: 38.6%p=0.05
RRR: 18.5%P=.23CREDO Overall
Steinhubl SR, et al: JAMA. 2002;288:2411-2420
CREDO Study: Timing of Loading Dose and 28-Day Endpoint
CREDO Study: Timing of Loading Dose and 28-Day Endpoint
Timing N Pretreat No Pretreat
3–<6 h 893 7.9 7.0
≥6–24h 851 5.8 9.4
Clopidogrel with PCIClopidogrel with PCI
• Pre-treatment effective if started > 6 hr before PCI
• No advantage to load dose >600 mg
• Beneficial effects evident out to 1 yr
• Optimal duration with DES unknown
• Pre-treatment effective if started > 6 hr before PCI
• No advantage to load dose >600 mg
• Beneficial effects evident out to 1 yr
• Optimal duration with DES unknown
Summary
LMWH with PCILMWH with PCI
Advantages of LMWH vs UFHAdvantages of LMWH vs UFH
• No platelet activation
• Inhibits von Willebrand factor release
• Augments TFPI release
• Inhibits thrombin generation
• No rebound hypercoagulability
• No platelet activation
• Inhibits von Willebrand factor release
• Augments TFPI release
• Inhibits thrombin generation
• No rebound hypercoagulability
Enoxaparin in the Cath Lab
In Cath LabTransition to Cath Lab
NICE 1
NICE 4
ELECT
Choussat
Carnendran
STEEPLE
NICE 1
NICE 4
ELECT
Choussat
Carnendran
STEEPLE
Collet
PEPCI PK study
NICE 3
SYNERGY
Collet
PEPCI PK study
NICE 3
SYNERGY
LMWH vs UFH in PCI TrialsLMWH vs UFH in PCI Trials
LMWH
n=3787
UFH studies
n=978
p
Efficacy EP 5.8% 7.6% 0.03
Major Bleed 0.6% 1.8% 0.0001
Minor Bleed 3.1% 3.1% ns
Pooled Results (15 studies)
Borentain, Montalescot: ESC 2003
Enoxaparin in PCI TrialsEnoxaparin in PCI Trials
Enox 0.5 n=798
Enox 0.75 n=1051
Enox 1.0 n=1226
p
Efficacy EP 1.8% 6.9% 6.6% 0.0001
All Bleed 2.3% 4.8% 3.9% 0.02
Pooled Results
Borentain, Montalescot: ESC 2003
IV enoxaparin0.5 mg/kg
n=1070
IV enoxaparin0.5 mg/kg
n=1070
STEEPLE TrialSTEEPLE Trial
IV enoxaparin0.75 mg/kg
n=1228
IV enoxaparin0.75 mg/kg
n=1228
3528 pts with non-emergent single or multi-vessel PCI
3528 pts with non-emergent single or multi-vessel PCI
ACT – adjusted UFH Target ACT 200-300 With GP IIb/IIIaTarget ACT 300-350 if no GP IIb/IIIa
n=1230
ACT – adjusted UFH Target ACT 200-300 With GP IIb/IIIaTarget ACT 300-350 if no GP IIb/IIIa
n=1230
Montalescot: NEJM 2006;355:1006-1017
Primary Endpoint: Major / minor bleeding (non-CABG) at 48 hrs post-PCISecondary Endpoints: - Percent reaching target anticoagulation levels at start and end of PCI - Composite of major bleed (48 hrs), mortality, MI, Urg TVR at 30 days
STEEPLE Trial: Primary EndpointSTEEPLE Trial: Primary Endpoint
6.0% 6.6%8.7%
0%
5%
10%
15%
20%Enox 0.5 mg/kg Enox 0.75 mg/kg UFH
6.0% 6.6%8.7%
0%
5%
10%
15%
20%Enox 0.5 mg/kg Enox 0.75 mg/kg UFH
Non-CABG Major or Minor Bleeding at 48 hrs
Lower bleeding rate was observed overall and in the GP IIb/IIIa subgroup
p=0.014 vs UFH
p=0.052 vs UFH
Montalescot: NEJM 2006;355:1006-1017
1.2% 1.2%
2.8%
0%
1%
2%
3%
4%
5%
Enox 0.5 mg/kg Enox 0.75 mg/kg UFH
1.2% 1.2%
2.8%
0%
1%
2%
3%
4%
5%
Enox 0.5 mg/kg Enox 0.75 mg/kg UFH
Analysis of Major Bleeding
STEEPLE TrialSTEEPLE Trial
57% lower with Enoxaparin
Montalescot: NEJM 2006;355:1006-1017
p=0.007vs UFH
p=0.005vs UFH
Patients reaching target anticoagulation levels at the start and end of procedure
78.8%91.7%
19.7%
0%
20%
40%
60%
80%
100%
Enox 0.5 mg/kg Enox 0.75 mg/kg UFH
78.8%91.7%
19.7%
0%
20%
40%
60%
80%
100%
Enox 0.5 mg/kg Enox 0.75 mg/kg UFH
STEEPLE Trial: Secondary Endpoint STEEPLE Trial: Secondary Endpoint
p<0.001 vs Enox
Montalescot: NEJM 2006;355:1006-1017
STEEPLE Trial STEEPLE Trial
• Reduced dose enoxaparin had less major or minor bleeding at 48 hrs than UFH
• Lower dose IV enoxaparin for PCI offers a safety advantage over ACT-guided UFH
• Reduced dose enoxaparin had less major or minor bleeding at 48 hrs than UFH
• Lower dose IV enoxaparin for PCI offers a safety advantage over ACT-guided UFH
Summary
• 10,027 ACS patients with 2 out of 3 high-risk criteria:
• Age > 60• (+) biomarkers• (+) ECG s
• Randomized to enoxaparin vs UFH• Invasive management strategy• GP IIb/IIIa antagonists encouraged• Primary endpoint : Death / MI at 30 days
• 10,027 ACS patients with 2 out of 3 high-risk criteria:
• Age > 60• (+) biomarkers• (+) ECG s
• Randomized to enoxaparin vs UFH• Invasive management strategy• GP IIb/IIIa antagonists encouraged• Primary endpoint : Death / MI at 30 days
Superior Yield of the New strategy of Enoxaparin, Revascularization &
GlYcoprotein IIb/IIIa Inhibitors
Superior Yield of the New strategy of Enoxaparin, Revascularization &
GlYcoprotein IIb/IIIa Inhibitors
The Synergy Investigators: JAMA 2004; 292: 45-54
SYNERGYSYNERGY
14.0 14.511.7 12.7
3.2 3.1
0
10
20
30
Death / MI MI Death
Enox (n=4992)
UFH (n=4982)
14.0 14.511.7 12.7
3.2 3.1
0
10
20
30
Death / MI MI Death
Enox (n=4992)
UFH (n=4982)
p=0.705
p=0.135p=0.396
%
Efficacy at 30 days
The Synergy Investigators: JAMA 2004; 292: 45-54
13.3
15.9
9.37.9
12.8
15.6
8.1 7.5
0
5
10
15
20
25
30d Death / MI TIMI MajorBleed
30d Death / MI TIMI MajorBleed
Enox
UFH
13.3
15.9
9.37.9
12.8
15.6
8.1 7.5
0
5
10
15
20
25
30d Death / MI TIMI MajorBleed
30d Death / MI TIMI MajorBleed
Enox
UFH
p=0.0029
RRR = 17.9%
p=0.0039
RRR = 16.4%
SYNERGYOutcomes with Consistent Therapy*
SYNERGYOutcomes with Consistent Therapy*
Per ProtocolIntent-to-treat
n=3398 n=2740 n=2627n=3010
* Consistent therapy = no pre-randomized therapy, or randomized to the same therapy they had been receiving
%
p=ns
p=ns
The Synergy Investigators: JAMA 2004; 292: 45-54
Bivalirudin
Direct Thrombin InhibitorsDirect Thrombin Inhibitors
Predictable anticoagulant response
Inhibits soluble and fibrin-bound thrombin
Inhibits thrombin-induced platelet aggregation
No HIT
Needs continuous infusion
No antidote
Cost
DisadvantagesAdvantages
Xiao Z, Theroux P: Circulation 1998;97:251-256
Direct Thrombin Inhibitors
REPLACE – 2ACUITY
Bivalirudin
REPLACE - 2REPLACE - 2
109.2
0.4 0.2
6.27
1.4 1.2
4.1
2.4
0
5
10
15
Composite Death MI Urg TVR MajorBleed
Heparin + GP 2b/3a (n=3008)Bivalirudin (n=2994)
109.2
0.4 0.2
6.27
1.4 1.2
4.1
2.4
0
5
10
15
Composite Death MI Urg TVR MajorBleed
Heparin + GP 2b/3a (n=3008)Bivalirudin (n=2994)
%Primary Endpoint
p=0.324
p=0.255
p=0.43
p=0.435p<0.001
REPLACE - 2REPLACE - 2
5.8 6.6
0.4 0.4
25.7
13.4
1.4 1.2 1.7 10
10
20
30
CK-MB Q MI MinorBleed
Transfuse Thrombo
Heparin + GP 2b/3aBivalirudin
5.8 6.6
0.4 0.4
25.7
13.4
1.4 1.2 1.7 10
10
20
30
CK-MB Q MI MinorBleed
Transfuse Thrombo
Heparin + GP 2b/3aBivalirudin
%Outcomes
p=ns
p=nsp=ns
p=ns
p<0.001
cytopeniacytopenia
REPLACE - 2REPLACE - 2
• Non-inferior to heparin + GP 2b3a receptor inhibitors
• Superior to heparin
• Reduced bleeding, transfusion, and thrombocytopenia
• Reduced time of treatment
• Non-inferior to heparin + GP 2b3a receptor inhibitors
• Superior to heparin
• Reduced bleeding, transfusion, and thrombocytopenia
• Reduced time of treatment
Conclusions
Moderate-to high-
riskACS
ACUITY Study Design:First Randomization
ACUITY Study Design:First Randomization
An
gio
gra
ph
y w
ith
in 7
2 h
Aspirin in all;Clopidogrel dosing
and timingper local practice
UFH or enox+ GP IIb/IIIa
n=4603
Bivalirudin+ GP IIb/IIIa
n=4604
Bivalirudinalone
n=4,612
R*
Moderate- to high-risk patients with UA or NSTEMIundergoing an invasive strategy (N = 13,819)
Medicalmanagement
PCI
CABG
Stone GW, et al: Am Heart J 2004; 148:764–775
*Stratified by pre-angiography thienopyridine treatment
11.7%11.8% 1.01 (0.90-1.12)<.001
.93
0 1 2
Risk ratio±95% CI
Risk ratio±95% CI
Primaryend point
ACUITY: Primary End Point Measures*ACUITY: Primary End Point Measures*UFH/Enoxaparin + GP IIb/IIIa vs Bivalirudin + GP IIb/IIIa
Net clinical outcome
Ischemic composite
Major bleeding
Bivalirudin + GP IIb/IIIa betterBivalirudin + GP IIb/IIIa better UFH/Enox + GP IIb/IIIa betterUFH/Enox + GP IIb/IIIa better
Bival+ IIb/IIIa
UFH/Enox+ IIb/IIIa
RR (95% CI)P value
(noninferior)(superior)
7.3%7.7% 1.07 (0.92-1.23).015.39
5.7%5.3% 0.93 (0.78-1.10)<.001
.38
Up
per
bo
un
dar
y n
on
-in
feri
ori
ty
Stone GW, et al: Presented at: 55th ACC Annual Meeting March 2006
*ITT population
0 1 2
ACUITY: Primary End Point Measures*ACUITY: Primary End Point Measures*
Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better
Risk ratio±95% CI
Risk ratio±95% CI
Primaryend point
Bivalalone
UFH/Enox+ IIb/IIIa
RR (95% CI)
Net clinical outcome
Ischemic composite
Major bleeding
Up
per
bo
un
dar
y n
on
-in
feri
ori
ty
11.7%10.1% 0.86 (0.77-0.97)<.001.015
7.3%7.8% 1.08 (0.93-1.24).02.32
5.7%3.0% 0.53 (0.43-0.65)<.001<.001
P value(noninferior)
(superior)
UFH/Enoxaparin + GP IIb/IIIa vs Bivalirudin alone
Stone GW et al: Presented at: 55th ACC Annual Meeting March 2006
*ITT population
ACUITY-PCI Net Clinical Outcomes
ACUITY-PCI Net Clinical Outcomes
0
5
10
15
0 5 10 15 20 25 30 35
Days from Randomization
Estimate p (log rank)
13.5%Heparin* + IIb/IIIa (N=2561)
Bivalirudin + IIb/IIIa (N=2609) 0.1015.1%
Bivalirudin alone (N=2619) 0.04911.7%
p=0.001
Stone GW: Presented at TCT; October 2006
%
ACUITY- PCIComposite Ischemia
ACUITY- PCIComposite Ischemia
0
5
10
15
0 5 10 15 20 25 30 35
Days from Randomization
Estimate p (log rank)
8.4%Heparin* + IIb/IIIa (N=2561)
Bivalirudin + IIb/IIIa (N=2609) 0.159.4%Bivalirudin alone (N=2619) 0.458.9%
p=0.36
Stone GW. Presented at TCT; October 2006
%
Anti-Thrombins for PCIAnti-Thrombins for PCI
• UFH is effective for PCI, especially when used with GP2b3a inhibition
• LMWH (enoxaparin) is safe and effective with PCI
• Bivalirudin is superior to heparin and non-inferior to heparin + GP 2b3a Rx
• UFH is effective for PCI, especially when used with GP2b3a inhibition
• LMWH (enoxaparin) is safe and effective with PCI
• Bivalirudin is superior to heparin and non-inferior to heparin + GP 2b3a Rx
Summary