Making sense of antithrombotic therapy in the cath lab

Azfar Zaman Freeman Hospital

BCIS Cardiff 2010

Risk profile for PCI

n  stable angina (mortality <0.25%)

n  unstable angina/NSTEMI (1-2%)

n  STEMI (4-7%)

Stable angina

n  preloaded with ASA and clopidogrel (600mg) at least 6 hours pre-procedure¹ (AHA/ACC IC)

n  which (if any) anticoagulant?

n  dose?

n  early mobilisation/day case

1. CREDO JAMA 2002;288:2411

Heparin’s limitations

Heparin exhibits a nonlinear dose-response

Heparin dose

Clo

tting

tim

e

Heparin

Coronary Interventions Antiplatelet-based Only (CIAO) Study

JACC 2008;52:1293

Simple type A lesions

Viswanathan G et al Cardiovascular Therapeutics (in press)

Viswanathan G et al Cardiovascular Therapeutics (in press)

Stable Angina

n  thrombus prevention : no or reduced anticoagulant

n  thrombus treatment : any GPI or bivalirudin

NSTE-ACS

n  no upstream treatment

Who benefits from GPI after 600mg clopidogrel loading?

n  stable

n  ACS

diabetes – X ISAR-SWEET¹

no diabetes X

NSTE – troponin negative X

NSTE – troponin positive √ ISAR REACT-2³

STEMI - ? 1 Circulation 2004:110;3527 2 NEJM 2004:350;232 3 JAMA 2006:295;1531

ISAR REACT²

Primary PCI – ASA only

ESC 2008 – Recommendations Class LOE

n  Antiplatelet co-therapy •  aspirin • clopidogrel loading dose •  GPI antagonist

n  abciximab n  tirofiban n  eptifibatide

n  Antithrombin co-therapy •  heparin •  bivalirudin •  fondaparinux

n  Adjunctive devices •  thrombus aspiration

I I

IIa IIb IIb I

IIa III

IIb

B C A B C C B B B

Primary PCI: Adjunctive therapies

ACC/AHA 2007 – Recommendations Class LOE n  Antiplatelet co-therapy

•  abciximab •  tirofiban • eptifibatide

n Antithrombin co-therapy •  heparin •  bivalirudin •  fondaparinux

IIa IIb IIb I I

III

A B C C C C

Primary PCI: Adjunctive therapies

In primary PCI, ReoPro delivers improvements in clinical outcomes

ReoPro improves 30-day clinical outcomes in primary PCI1–5

D = death; MI = myocardial infarction; TVR = target vessel revascularization; UTVR = urgent target vessel revascularization

RAPPORT1 CADILLAC2 ISAR-23 ADMIRAL4 ACE5

Placebo + PTCA (n=242) ReoPro + PTCA (n=241)

PTCA or stent (n=1030) ReoPro + PTCA or stent (n=1052)

Usual care + stent (n=200) ReoPro + stent (n=201)

Placebo + stent (n=151) ReoPro + stent (n=149)

Stent alone (n=200) ReoPro + stent (n=200)

p=0.03

p=0.01

p=0.038

p=0.01

p=0.023 11.2

5.8 7.0

4.6

10.5

5.0

14.6

6.0

10.5

4.5

Pat

ient

s (%

)

30 days D/MI/UTVR

30 days D/MI/TVR/stroke

30 days D/MI/TVR

30 days D/MI/UTVR

30 days D/MI/TVR/stroke

20-

18-

16-

14-

12-

10-

8-

6-

4-

2-

0-

1.  RAPPORT. Circulation 1998;98:734–41. 2. CADILLAC. Circulation 2003;108:1316–23. 3. ISAR-2. J Am Coll Cardiol 2000;35:915–21. 4. ADMIRAL. N Engl J Med 2001;344:1895–903. 5. ACE. J Am Coll Cardiol 2003;42:1879–85.

Stone G et al. N Engl J Med 2008;358:2218-2230

HORIZONS-AMI: Bivalirudin Alone v Heparin plus GPIIb/IIIa

Three-Year All-Cause Mortality

P=0.03

3-yr HR [95%CI]= 0.75 [0.58, 0.97]

5.9%

7.7% A

ll-C

ause

Mor

talit

y (%

)

0 1 2 3 4 5 6

9 10

1611 1568

1660 1689 1670

1800 Bivalirudin alone

0 12 15 18 21 24 27 30 33 36

1098 1802 1643

Months 3 6 9

Number at risk

Heparin+GPIIb/IIIa 1633 1593

1574 1525 1043

0.71 [0.51, 0.98] P=0.04

1-yr HR [95%CI]=

Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802)

7 8

4.8%

3.4%

TCT Washington 2010

What’s new?

Oral antiplatelets in STEMI

n  TRITON¹ (STEMI 26%) [prasugrel]

n  PLATO-INVASIVE² (49.1%) [ticagrelor]

n  CURRENT – OASIS³ (29.2%) [clopidogrel]

1.  Montalescot et al Lancet. 2009;373:723 2.  Cannon et al Lancet. 2010;375:283 3.  Mehta et al N Engl J Med. 2010;363:930

R Angiograpy TRITON

Prasugrel LD 60mg + MD 10mg

PCI

Clopidogrel LD 300mg + MD 75mg

R

Ticagrelor 180mg + MD 90mgx2

PCI PLATO

Clopidogrel LD 600mg (16%)

R CURRENT

Angiograpy

PCI Angiograpy

99%

Clopidogrel LD 300mg + MD 75mg

Clopidogrel LD 300mg + MD 75mg

Clopidogrel LD 600mg + MD 150mg

81% 64.3%

70%

99% n= 13,608

n= 18,624

n= 25,087

100%

Zaman et al ATVB 2000:20:860

B

OVERALL

No GPI GPI

DES BMS

DM No DM

>75 65-74

<65

Female Male

STEMI UA/NSTEMI

0.5 1 2 Prasugrel Better Clopidogrel Better HR

Age

Reduction in risk (%) 18

21 12

25 14 6

14 30

20 18

21 16

19

21

Pinter = NS

CV Death, MI, Stroke Major Subgroups

CrCl > 60 CrCl < 60 14

19

Montalescot et al Lancet 2009;373:723

Prasugrel v Clopidogrel in STEMI : 30 day endpoints

Prasugrel v Clopidogrel in STEMI : 15 month endpoints

PLATO – Invasive Lancet 2010;375:283

0.50 1.50

Overall NSTEMI/UA STEMI Male Female Age <= 65 yrs Age > 65 yrs Non-Diabetic Prev Diabetic No Inhosp GPIIb/IIIa GPIIb in hosp No Prot Pump Inhib Prot Pump Inhib Non-smoker Current Smoker ASA Low ASA High

17232 10886 6346 13009 4223 10975 6257 13400 3831 12288 4936 7675 5557 10845 6380 8620 8612

4.5 4.2 5.0 4.1 5.8 3.0 7.1 4.2 5.6 3.9 6.0 3.8 5.7 4.9 3.8 4.2 4.8

3.9 3.6 4.2 3.6 4.6 2.7 6.0 3.6 4.9 3.5 4.7 3.2 4.2 4.6 2.6 4.3 3.5

0.805 0.419 0.702 0.836 0.465 0.408 0.045 0.024

0.50 1.50

3.7 3.6 4.0 3.5 4.6 2.9 5.2 3.6 4.1 3.1 5.2 3.1 4.8 3.9 3.4 3.6 3.8

3.0 3.1 2.8 3.0 3.0 2.2 4.4 2.8 3.6 2.5 4.1 2.3 3.3 3.5 2.1 3.2 2.7

0.248 0.148 0.418 0.567 0.894 0.613 0.050 0.191

CV Death, MI or Stroke MI or Stent thrombosis

Clopidogrel: Double v Standard Dose PCI Cohort Subgroups

Std % Double % Std % Double % Intxn P Intxn P

Double Dose Better

Double Dose Better

Std Dose Better

Std Dose Better

2N

Mehta S, ESC 2009

Days

Cum

ulat

ive

Haz

ard

0.0

0.01

0.

02

0.03

0.

04

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients

Clopidogrel Standard

Clopidogrel Double

HR 0.85 95% CI 0.74-0.99

P=0.036

15% RRR

CV Death, MI or Stroke

Mehta S, ESC 2009

Anticoagulants in STEMI

n  unfractionated heparin – no randomised controlled trials (ESC = IC)

n  low molecular weight heparin - ATOLL¹

1.  Montalescot et al presented at ESC Stockholm 2010

ATOLL

Trial of UFH v LMWH in primary PCI [ESC Stockholm 2010]

Antithrombotics in the cath lab: summary

n  in stable angina : nil

n  in ACS : GPI or bivalirudin for troponin positive only

n  in STEMI : prasugrel/ticagrelor (low dose UFH or LMWH)

GPI/bivalirudin for visible thrombus after aspiration

Thank you

Copyright restrictions may apply.

Krumholz, H. M. et al. JAMA 2009;302:767-773.

Change in Acute Myocardial Infarction 30-Day All-Cause Risk-Standardized Mortality From 1995 to 2006

18.8% (SD, 2.1%; range, 10.4%-27.5%) in 1995

15.8% (SD, 1.7%; range, 10.6%-21.6%) in 2006

Intravenous antiplatelet therapy in STEMI - timing

APEX-AMI trial – retrospective analysis of patients receiving glycoprotein inhibitors revealed that preprocedure infusion significantly improved 90 day outcomes

1.  Eur Heart J. 2010 Jul;31(14):1708-16. 2.  JAMA. 2007;297:43