interventional pharmacology: the basics michael j. cowley, facc,fscai nothing to disclose

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 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)


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


PTCA or StentPTCA or StentN = 2082N = 2082


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


n=1070

STEEPLE TrialSTEEPLE Trial


n=1228


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


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%


Analysis of Major Bleeding

STEEPLE TrialSTEEPLE Trial

57% lower with Enoxaparin


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%


78.8%91.7%

19.7%

0%

20%

40%

60%

80%

100%


STEEPLE Trial: Secondary Endpoint STEEPLE Trial: Secondary Endpoint

p<0.001 vs Enox


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


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


Enox

UFH

13.3

15.9

9.37.9

12.8

15.6

8.1 7.5

0

5

10

15

20

25



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


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


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


• 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

interventional pharmacology: the basics michael j. cowley, facc,fscai nothing to disclose

Documents

complex lesions p

clinical experience

accahascai pci guidelinesufh

numerous studies vs

clinical trialsnewby

day death mi

going pci level of evidence

pbenefits of gp iibiiia