1) Aspirin, P2Y12 inhibitors (ticagrelor, prasugrel, clopidogrel), and heparin are used to treat acute myocardial infarction. Aspirin and P2Y12 inhibitors prevent platelet aggregation while heparin inhibits thrombin. 2) Clinical trials have shown that aspirin reduces mortality and reinfarction rates compared to placebo. P2Y12 inhibitors like ticagrelor and prasugrel are more effective than clopidogrel but increase bleeding risk. 3) Fibrinolytics like tenecteplase can be used when primary PCI is not available within 120 minutes to reperfuse the infarcted area through

1. Antiplatelets and Anticoagulation
in Acute Myocardial Infarction
Shane Colliss MBBS BScHons
Sir Charles Gairdner Hospital – ED Education
4 December 2014

3. Medications
• Aspirin
• Ticagrelor or
Prasugrel or
Clopidogrel
• Heparin

4. Thromboxane A2 - Prostacyclin Balance
• Both produced by cyclooxygenase pathway
• Thromboxane A2 (Platelets)
– Promotes vasoconstriction
– Promotes platelet aggregation
• Prostacyclin (Endothelium)
– Inhibits platelet aggregation
– Promotes vasodilation

5. Aspirin
• Aspirin causes irreversible inhibition of COX
– Endothelial cells produce new COX within hours
– Platelets cannot synthesise new COX
• Platelet half life 4 days
• Balance shifted towards prostacyclin effects of
inhibition of platelet aggregation (and
vasodilation)

6. Aspirin
• Prevents platelet aggregation
by inhibiting production of
thromboxane A2
• Antiplatelet activity discovered
in 1971
• STEMI:
– 300mg Aspirin PO
• Enteric coated aspirin must be
crushed or chewed if used as a
loading dose
Sir John Vane (1927-2004)
http://upload.wikimedia.org/wikipedia/
commons/thumb/e/e3/John_Robert_Vane.jpg/
640px-John_Robert_Vane.jpg

7. Aspirin
• Second International Study of Infarct Survival
(ISIS2)(Lancet 1988)
– 17,187 patients given 30 days of treatment with
162mg aspirin vs placebo starting within 24hours of
onset of AMI symptoms
– Risk reduction at 5 weeks:
• Vascular mortality – 23%
• Non-fatal reinfarction – 49%
• Non-fatal stroke – 46%
– No increase in haemorrhagic stroke or GI bleeding
– Small increase in minor bleeding

8. P2Y Receptors
• ADP receptors found on most tissue
• G protein coupling
• P2Y12 found mainly on the surface of platelets
Dorsam RT, Kunapuli SP (2004). "Central role of the P2Y12 receptor in platelet activation". J. Clin. Invest. 113 (3): 340–5

9. Ticagrelor (Brilinta)
• Reversibly binds ADP
receptor antagonist on P2Y12
resulting in ADP mediated
prevention of platelet
activation and aggregation
• More rapid onset and more
profound antiplatelet activity
compared with Clopidogrel
• STEMI:
– Ticagrelor 180mg PO
• 2x 90mg tablets
http://www.signspecialist.com/decals/
mascot2/images/Tiger%20Claws.jpg

10. Ticagrelor
• Contraindications
– Heart rate <50
• Potential for inducing bradyarrhythmia and ventricular
pauses
– History of CVA/TIA/ICH

11. Ticagrelor
• Ticagrelor versus Clopidogrel in patients with
acute coronary syndromes (Wallentin et al. N Engl J
Med. 2009;361(11):1045)
– 18,624 patients double-blinded and randomised to
Ticagrelor 180mg loading dose (90mg BD
maintenance) or Clopidogrel 300-600mg loading dose
(75mg daily maintenance)
– Death from vascular cause (MI or CVA) (Primary
Endpoint)
• Ticagrelor 9.8% vs Clopidogrel 11.7%
– Ticagrelor associated with higher rate of major
bleeding including fatal intracranial bleeding

12. Ticagrelor
• Prehospital Ticagrelor in ST-Segment Elevation
Myocardial Infarction (Montalescot et al. N Engl J Med.
2014 Sep)
– 1,862 patients with STEMI were randomized to
prehospital or in-hospital ticagrelor loading
– No significant difference in major adverse
outcomes
– Reduced rate of stent thrombosis in prehospital
ticagrelor group (0% vs 0.8% in the first 24hours,
0.2% vs 1.2% at 30 days)

13. Ticagrelor
• Comparison of prasugrel and ticagrelor loading
doses in ST-segment elevation myocardial
infarction patients: RAPID (Rapid Activity of
Platelet Inhibitor Drugs) primary PCI study. (Parodi
et al. J Am Coll Cardiol. 2013;61(15):1601.)
– Monitored the action of the two antiplatelet
medications over 12hrs in 50 patients with STEMI.
– Both drugs were effective platelet inhibitors in only
half the patients at 2hrs, but effective in most patients
at 4hrs.
– Morphine delayed the onset of antiplatelet activity.

14. Prasugrel (Effient)
• Inhibits platelet activation and aggregation
through irreversibly binding its active
metabolite to the P2Y12 ADP-receptor s on
platelets
• Peak plasma concentration
• STEMI:
– 60mg Prasugrel PO
• 6x 10mg tablets

15. Prasugrel
• Contraindications
– Weight < 60kg
– Age > 75
– History of TIA/CVA/ICH
– End stage kidney disease

16. Prasugrel
• Prasugrel versus clopidogrel in patients with acute
coronary syndromes. (Wiviott et al. N Engl J Med.
2007;357(20):2001.)
– 13,608 patients with moderate-high risk ACS were
randomly assigned to receive prasugrel (60mg loading and
10mg daily maintenance) or clopidogrel (300mg loading
and 75mg daily maintenance)
– Prasugrel associated with significantly reduced rates of
ischaemic events (9.9% vs 12.1%), but with in increased
risk of major bleeding (including fatal bleeding 0.4% vs
0.1%).
– No significant mortality difference between the groups.

17. Clopidogrel (Plavix)
• Inhibits platelet activation and aggregation
through irreversible binding of its active
metabolite to platelet P2Y12 ADP-receptors
• STEMI:
– 600mg Clopidogrel PO
• 8x 75mg tablets

18. Clopidogrel
• Addition of clopidogrel to aspirin and fibrinolytic
therapy for myocardial infarction with ST-segment
elevation. (Sabatine et al, N Engl J Med.
2005;352(12):1179)
– 3,491 patients aged 18-75yrs presenting within 12hrs
of onset of STEMI were randomly assigned to receive
300mg clopidogrel loading dose (75mg daily
maintenance) or placebo, as well as aspirin loading
and fibrinolysis
– Primary efficacy endpoint of death, occluded infarct-related
artery or recurrent MI before angiography
(performed 48-192hrs after medications commenced)
• Placebo 21.7% vs Clopidogrel 15.0% (=36% risk reduction)

19. Clopidogrel
• Addition of clopidogrel to aspirin in 45,852
patients with acute myocardial infarction:
randomised placebo-controlled trial. (Chen et al.
Lancet. 2005 Nov;366(9497):1607-21.)
– 45,852 patients with suspected MI (93% STEMI or
BBB, 7% NSTEMI) and randomized to placebo or
Clopidogrel 75mg daily continuing until discharge or
up to 4 weeks
– Clopidogrel group had 9% relative reduction in death,
reinfarction or stroke (9.2% vs 10.1%)
– Significant bleeding (transfusion, cerebral or fatal)
rates were 0.58% (clopidogrel) vs 0.55% (placebo)

20. Antithrombin III
• Circulating protease inhibitor
• Binds to proteases in the coagulation system
– Blocks their activity as clotting factors
• Most important: Thrombin (IIa), IXa, Xa
• Heparin increases rate of reaction by 1000x

21. Heparin
• Combines with
antithrombin III to
inhibit thrombosis by
inactivating activated
factor X and
inhibiting the
conversion of
prothrombin to
thrombin
• STEMI:
– 5000IU Heparin IV http://www.aafp.org/afp/2001/0801/afp20010801p419-f1.gif

22. Heparin
• Clinical effects of anticoagulant therapy in suspected acute
myocardial infarction: systematic overview of randomised
trials. (Collins et al. BMJ. 1996;313(7058):652.)
– Meta-analysis of 27 trials using oral antiplatelets and IV or
subcut heparin. 68,000 patients received aspirin with the other
medications. 5000 patients did not receive aspirin.
– In the absence of aspirin – anticoagulant therapy reduced
mortality by 25% (35 fewer deaths per 1000). In the presence
of aspirin – heparin use reduced mortality by 6% (5 fewer per
1000).
– “The clinical evidence from randomised trials does not justify
the routine addition of either intravenous or subcutaneous
heparin to aspirin in the treatment of acute myocardial
infarction (irrespective of whether any type of fibrinolytic
therapy is used)”

23. Heparin
• Unfractionated heparin and low-molecular-weight
heparin in acute coronary syndrome
without ST elevation: a meta-analysis (Eikelboom et
al The Lancet 2000 June 355:9212 1936-1942)
– In 12 trials of 17,157 patients receiving short term
unfractionated or LMWH were compared with
placebo.
– Patients treated with aspirin and heparin or LMWH
had half the risk of death and MI.
– Patients treated for longer than 7 days with heparin
had a significant increase in major bleeding risk.

24. Uh oh!
• ED Reg: 55 “STEMI ED NOW”
• Cardiology Reg: “The cath lab staff are all at
tea for the next hour and a half. Is that a
problem?”

25. tPA
2013 ACCF/AHA Guideline for the Management
of ST-Elevation Myocardial Infarction. (Practice
Guideline January 2013. http://content.onlinejacc.org/article.aspx?articleid=1486115 )
• “In the absence of contraindications,
fibrinolytic therapy should be given to
patients with STEMI and onset of ischemic
symptoms within the previous 12 hours when
it is anticipated that primary PCI cannot be
performed within 120 minutes of first medical
contact”

26. Tissue –type plasminogen activator
• Plasmin = fibrin specific protease
– Fibrinolysis, thrombus remodelling, limits
extension of clot
– Precursor plasminogen is activated by thrombin
and tPA to produce plasmin

27. Reteplase (Rapilysin)
• Recombinant tPA cleaves plasminogen to form plasmin to
degrade fibrinogen and fibrin
• Dominant half life 18±5 minutes
• Use:
– <12h STEMI, New LBBB
– Prehospital/Cath lab unavailable
• 10U bolus of reteplase, repeat 10U at 30mins
• Contraindications:
– Bleeding risk
– “recent (< 10 days) prolonged and vigorous external heart
massage” (from mimsonline)