pharmacology in acute coronary syndromes: anti-platelet agents tim kinnaird, university hospital...

Pharmacology in Acute Coronary

Syndromes: Anti-platelet AgentsTim Kinnaird, University Hospital Wales, Cardiff and Vale NHS Trust

NO CONFLICT OF INTEREST TO DECLARE

Intra-Coronary Thrombus

Tim Kinnaird

We're all aware of the difficulties presented by these appearances and therefore antiplatelet agents are a crucial component of adjuctive therapy adminstered during PCI for ACS.

What are the Characteristics of an Ideal Anti-Platelet Agent?

• Effective

• Rapid Onset

• Safe

• Cheap

• Works in all patients

• Rapid Offset

Tim Kinnaird

The ideal antiplatelt agent should be ......For the purposes of this morning I am going to concentrate on the effectiveness and timing of currently available antiplatelet agents.

Effectiveness of Clopidogrel

PCI-Cure, Credo, PCI-Clarity meta-analysis (7000 patients vast majority presented with ACS)

JAMA 2005;294:1224-1232

Tim Kinnaird

Metanalysis of almost 7000 pts comparing preloading and pretreament with 300mg clopi compared to control.


Circulation. 2005;112:2946-2950


Circulation 2005;111:2099-106

255 patients (25% ACS) preloaded 300 vs. 600mg 4-8hrs pre PCI


292 ACS pts 300 vs. 600mg clopidogrel at least 12-hours pre PCI

JACC 2006;48:1339-45

Tim Kinnaird

Further work comparing 300 and 600 in acs pts undergoing PCI. 300 and 600 given at least 12-hours before PCI as well as demonstrating better plat inhibition clearly demonstrated a very impressive clinical benefit at 30days. (35% tirofiban use in both groups)

What are the Characteristics of an Ideal Anti-Platelet Agent?

• Effective

• Rapid Onset

• Safe

• Cheap

• Works in all patients

• Rapid Offset

Onset of Action of Clopidogrel

Mean 9.8hrs

CREDO

Median 10 days

PCI-Curep=NS

300mg load and pre-treatment


Early and Sustained Dual Oral Antiplatelet Therapy Following Percutaneous Coronary Intervention: Clopidogrel for Reduction in Events During Observation (CREDO) trial

JAMA 2002;288:2411-20

JACC 2006;47:939-43

Tim Kinnaird

...can conclude that unless you can afford to wait 15-hours before performing PCI that 300mg of clopidogrel is insufficient therapy.

ALBION study

In-vitro analysis


JACC 2006;48:931-8

Tim Kinnaird

Albion investigators examined effect of 300, 600 and 900mg clop on platelt function and clinical outcomes in 103 pts with ACS. Tantalising clinical data suggesting benefit at 30days but small numbers and thus not significant


2159 low and moderate risk patients, ACS excluded

Preload with 600mg at least 2-hours before PCI

NEJM 2004;350:232-8 JACC 2004;44:2133-36

Tim Kinnaird

Subsequent study demonstarted similar results even with very brief pretreatment intervals. although not directly comparing preload timing these data do imply that excellent platelet inhibition is achieved if 600 given >2hours in stable low/mod risk pci. However should not be extrapolated to acs particulalry as pt activated in acs.


2022 pts with NSTEACS

600mg clopidogrel at least 2-hours pre PCI

JAMA 2006;295:1531-38

Armyda 5

• 600mg clopidogrel 6-hours pre-PCI vs. 600mg clopidogrel after diagnostic angiogram

• Prelim data presented suggested no difference between 2 groups

• Full peer review data at ACC late-breaking trials

What do the Guidelines Say About Clopidogrel Pretreatment in PCI for ACS?

ESC 2005 guidance states:ACC/AHA/SCAI 2005 guidance states:

Circulation 2006;113;156-175

ISAR-REACT

ISAR-REACT

CREDO

CURE

PCI-CURE

Different question

Different question

WHAT WE KNOW WE KNOW

- 300mg loading dose should be given at least 15-hours before PCI in ACS patients

- 600mg dose is probably more effective than 300mg dose

- troponin +ve ACS pts should receive abciximab in addition to 600mg of clopidogrel regardless of timing

CONCLUSIONS

WHAT WE KNOW WE DON’T KNOW

- what is the optimal timing of 600mg dose of clopidogrel in ACS patients undergoing PCI

- whether early enough loading with 600mg clopidogrel would obviate the need for further adjunctive antiplatelet agents

- whether higher still doses of clopidogrel are better

CONCLUSIONS

FINALLY

Newer oral antiplatelet agents include:

Prasugrel (thienopyridine)

Cangrelor (ADP analogue)

AZD6140 (direct inhibitor of P2Y12 receptor)

SCH530384 (PAR blocker)

Prasugrel as an Alternative to Clopidogrel

JUMBO-TIMI 26904 patients in safety study

Circulation 2005;111:3366-73

300

Less non-responders

More rapid onset to greater levels of IPA

Prasugrel as an Alternative to Clopidogrel

TRITON TIMI-38

13,000 ACS patients undergoing PCI

Randomised to prasugrel 60/10 or clopidogrel 300/75

Loading dose given between randomisation and completion of PCI

Primary endpoint time to first CV death, MI or CVA

Results expected 2008

pharmacology in acute coronary syndromes: anti-platelet agents tim kinnaird, university hospital...

Documents