What Needs Still Remain with Currently Available Antiplatelets

1
What Needs Still Remain with Currently Available
Anti-platelets?

• Kurt Huber, MD
• 3rd Medical Department,
• Cardiology and Emergency Medicine,
• Wilhelminenspital,
• Vienna, Austria

2
Points of discussion

• Clopidogrel
• Loading dose
• Maintenance dose
• Resistance/low responsiveness
• Timing of application in ACS
• Duration of dual antiplatelet therapy after DES
• New thienopyridines
• Glycoprotein IIb/IIIa blockers
• Early use in STEMI (facilitated PCI)

ACS, acute coronary syndromes DES, drug-eluting
stent STEMI, ST-segment elevation myocardial
infarction.
3
ALBION Clopidogrel 600 mg provides more rapid
inhibition of platelet aggregation
103 patients with NSTE ACS randomised to receive
300, 600 or 900 mg clopidogrel
50
5 µmol/L ADP
900 mg
40
600 mg
900 mg

Inhibition of plateletaggregation ()
300 mg
30
600 mg

20
300 mg
10
P lt0.05 vs 300 mg
0
0
1
2
3
4
5
6
Time (hours)
Greater loading doses are associated with a
significantly faster onset of inhibition
ADP, adenosine diphosphate NSTE ACS,
non-ST-elevation acute coronary syndromes.
Montalescot G et al. JACC 2006489318.
4
Clopidogrel 600 mg vs 300 mg loading dose
292 consecutive NSTE ACS stent patients received
300 or 600 mg loading dose of clopidogrel
100
12.5
600 mg
300 mg
95
10.0
600 mg
90
7.5
P lt 0.0024
Events ()
CV event-free survival ()
85
5.0
300 mg
80
2.5
0
CVevents
Stroke
30
20
10
0
ACSevents
ST
CVdeath
Time (days)
Using a loading dose of clopidogrel 600 mg
reduced the occurrence of events vs 300 mg
CV, cardiovascular NSTE ACS, non-ST-elevation
acute coronary syndromes ST, stent thrombosis.
Cuisset T et al. J Am Coll Cardiol
200648133945.
5
Impact of early clopidogrel therapy on
in-hospital mortality in STEMI in the ACOS
Registry
Aspirin
Aspirin clopidogrel

18
15.6
16
14
12.4
12
9.7
9.4
9.3
10
8
5.6
5.1
6
4.2
4
2
0
Total
No reperfusion
Lysis
Primary PCI
PCI, percutaneous coronary intervention STEMI,
ST-elevated myocardial infarction.
Zeymer U et al. Eur Heart J 20062726616.
6
CIPAMI Study design
n 327 Clopidogrel 600 mg
Treatment according to investigator
n 654 with STEMI Acute STEMI lt6h Angina gt20
min ST elevation gt2 leads or new/presumed LBBB
Primary angiography Primary endpoint
(Secondary endpoints) Death, Re-MI, TVR
PCI
R
Aspirin UFH/enoxaparin
n 327 No loading
Clopidogrel loading prior to PCI strongly
recommended
LBBB, left bundle branch block MI, myocardial
infarction PCI, percutaneous coronary
intervention STEMI, ST-elevation myocardial
infarction TVR, target vessel revascularisation
UFH, unfractionated heparin.
Zeymer U et al. Cardiology 200710826572.
7

• 15-45 clopidogrel resistance
• Point of Care Platelet Function Tests?
• How to treat hypo-responsiveness?

8
US'real world' The PREMIER Registry

• 500 patients with acute MI treated by DES
  implantation received combined anti-platelet
  treatment clopidogrel on top of aspirin
• 30 days after implantation interview for
  discontinuation of clopidogrel
• 13.6 (68 patients) had discontinued
  clopidogrel. These patients were compared with
  patients who continued combined therapy at 12
  months
• One out of seven MI patients no longer took
  clopidogrel by 30 days, which was associated with
  an (adjusted) 9-fold increased risk to die within
  12 months

10
Discontinued
Continued
7.5
Mortality ()
5
P lt0.001
0.7
0
0
2
4
6
8
10
12
Months
Patients at risk
Continued
431
431
431
431
430
429
420
Discontinued
68
68
67
66
65
65
62
DES, drug-eluting stent MI, myocardial
infarction.
Spertus JA et al. Circulation 200611328039.
9
DISPERSE Faster, greater and more consistent IPA
with AZD6140 vs clopidogrel
Clopidogrel
AZD6140 (100 mg bid)
Day 1
Day 14
Day 1
Day 14
100
100
80
80
60
60
Inhibition ()
Inhibition ()
40
40
20
20
0
0
8
12
8
12
24
8
12
8
12
24
4
2
4
2
4
2
4
2
Time (hours)
Time (hours)
IPA, inhibition of platelet aggregation.
10
Glycoprotein IIb/IIIa inhibitors for PCI in AMI
More benefit in higher risk cohorts
100
80
ACE
ADMIRAL
60
Mortality reduction in abciximab group ()
40
ISAR-2
CADILLAC
20
RAPPORT
0
0
5
10
15
Mortality in placebo group at 1 year ()
AMI, acute myocardial infarction PCI,
percutaneous coronary intervention.
11
TIMI 3 patency before primary PCI in randomised
trials
TIMI 3 Flow ()
Early
Late or no GP IIb/IIIa blocker use
70
60
60
50
40
34
32
32
29
30
27
25
20
19
17
20
16
16
15
11
14
10
10
8
10
7
5
2
0
Zorman
ERAMI
ADMIRAL
TIGER-PA
INTAMI
TNK
TITAN
Reo-Mobile
ReoPro-
Cutlip
On-TIME
bridging
Tirofiban
Integrilin
Lysis
Abciximab
GP, glycoprotein PCI, percutaneous coronary
intervention.
12
Facilitated PCI with abciximabMeta-analysis
of six trials
Event rate ()
Early (n 260)
Late (n 342)
6
5.3
4.7
4.6
5
3.8
3.5
4
2.7
3
2
0.9
0.8
1
0
Death
Re-MI
TVR
Bleeding
MI, myocardial infarction PCI, percutaneous
coronary intervention TVR, target vessel
revascularisation.
13
FINESSE did not prove the hypothesisthat
facilitation of primary PCI with either
Abciximab alone or Abciximab in combination with
a 1/2 dose lytic improves the clinical outcome
Facilitation may be finished by FINESSEESC
Congress News, Sept 4, 2007
14
Summary

• Issues still remaining that need to be resolved
  in the near future are
• Loading and maintenance doses of clopidogrel
• Most reliable platelet function assay
• Time point of initiation of anti-platelet agents
  in patients with non-ST-elevation myocardial
  infarction or ST-elevation myocardial infarction
• Duration of combined anti-platelet therapy after
  drug- eluting stents
• Development and clinical proof (efficacy and
  safety) of new anti-platelet agents