A Broad Overview of Antiplatelet Therapy

ASPIRIN  ( patented: 1899)
Mechanism:   Acetylation of platelet cyclooxygenase prevents synthesis of Thromboxane A₂, (a prostaglandin derivative) which is a potent vasoconstrictor, and inducer of platelet aggregation and platelet release reaction.  Aspirin inhibits platelet aggregation for the life of the platelet (7 to 10 days).
 
Men benefit more: cardiovascular protection
Women benefit more: stroke prevention
Dosage: American Heart Assn. Recommends 75mg to 325mg/ day
Adverse effects & contraindications: GI bleeding. Avoid with asthma.
Drug interactions: Warfarin (however, this may be beneficial)
Drug monitoring: check for signs and symptoms of bleeding such as dark stools
Patient education: Take with food. Use enteric coated tablets.  Take low dose.
 
Thienopyridines
Mechanism:  inhibits platelet aggregation and activation by blocking the P2Y₁₂ adenosine diphosphate (ADP) receptor on the platelet surface. This inhibition is irreversible and lasts throughout the lifespan of the platelet (5-7 days). 
Clopidogrel (Plavix®)            
75mg tablets (FDA approved 1997)
Dosage: one tablet (75mg) daily, with or without food.
Clopidogrel is a pro-drug needing activation by the CYP450-2C19 pathway.
 

• Indicated for recent MI, or stroke, or established peripheral arterial disease. Reduces the rate of new ischemic stroke, new MI and other vascular deaths.
• Acute coronary Syndrome (ACS): for patients with acute coronary syndrome (unstable angina, non-Q-wave MI) including patients who are managed medically and those to be managed with percutaneous coronary intervention (with or without stent) or Coronary Artery Bypass Grafting (CABG)
• Mechanism:  inhibits platelet aggregation for the life of the platelet (5-7 days)

 
Adverse effects: increased bleeding risk
Contraindications: active bleeding (GI) or intracranial hemorrhage
Drug interactions: administer with caution for NSAID patients (increased GI bleeding risk)

• About 30% of Caucasians are poor CYP450- 2C19 metabolizers.
• Omeprazole (Prilosec®) blocks this pathway and may reduce effectiveness of clopidogrel.  Pantoprazole (Protonix®) is the least likely in this drug class to interact

Patient education: Discontinue 7-10 days before surgery if so directed. Most clinicians when combining with aspirin, will use the 81mg (low dose). 
In some cases, there is no benefit to aspirin/clopidogrel than aspirin therapy alone:

• Cardiovascular risk factors only:          aspirin + clopidogrel: combo NOT beneficial
• Established cardiovascular disease:    aspirin + clopidogrel: combo NOT beneficial
• Acute coronary syndrome:                    aspirin + clopidogrel: combo is beneficial
• After a stent:                                            aspirin + clopidogrel: combo is beneficial

 
Prasugrel (Effient®)        
FDA approved in 2009        
Prasugrel seems to be more effective than clopidogrel for reducing cardiovascular events in some acute coronary syndrome patients undergoing angioplasty. Carries a higher bleeding risk than clopidogrel.
Compared to clopidogrel: 

• Higher bleeding risk. Avoid in patients with prior TIA or prior stroke.
• not affected by 2C19 activation (minimal drug interactions with omeprazole)
• combine with aspirin after angioplasty
• avoid if over 75, unless high risk
• more effective than clopidogrel after angioplasty-more bleeding!
• Discontinue 7 days before surgery

Dosage: 5mg per day if under 60kg              10mg if over 60kg
 
Ticagrelor (Brilinta®)   
90mg tablets      FDA approved:2011      

• More effective than clopidogrel, and similar bleeding risk.
• Should take Aspirin 81mg, however don’t exceed 100mg. Loss of efficacy.
• Faster onset than clopidogrel (is NOT a prodrug)
• Reversibly binds to platelets, wears off faster than clopidogrel and prasugrel

 
WHEN A PATIENT RUNS OUT OF REFILLS.  MAJOR RISK!!
 
What about STOPPING aspirin, clopidogrel, prasugrel, and ticagrelor? The first challenge is no clear evidence determines the most effective duration for dual antiplatelet therapy (DAPT) after drug-eluting stents.
Risk of stopping aspirin, clopidogrel, or other antiplatelet drugs too soon:
NOTE: serious consequences can occur for patients on aspirin for secondary prevention, or on aspirin plus clopidogrel for acute coronary syndrome or after a stent, if they stop their drug therapy too soon.
Platelet rebound effect-Stopping Aspirin therapy:

• Stopping aspirin even short-term may increase the risk of heart attack and stroke possibly due to a rebound effect.
• Stopping aspirin seems to stimulate the production of new platelets and increase binding of fibrinogen. This rebound effect lasts at least 8 to 10 days after stopping therapy.
• More surgeons will continue aspirin if bleeding risk is low especially if the patient’s risk of thrombosis is high.
• Aspirin prevents clotting while it is being taken, but abruptly stopping it triples the risk of stroke and increases the risk of other cardiovascular adverse effects.
• Stopping aspirin in patients with a prior MI leads to 4 extra MIs per 1000 patients per year.
• Stopping clopidogrel (Plavix®) within 30 days after a drug-eluting stent results in 25% of patients having a stent thrombosis instead of just 1%.
• For stents, continue aspirin plus clopidogrel (Plavix®), prasugrel (Effient®), or ticagrelor (Brilinta®):
  • 30 days after a bare metal stent
  • 1 year after a drug eluting stent
  • Many clinicians will keep patients on dual therapy longer if the bleeding risk is low

 
CONTINUE ASPIRIN INDEFINITELY!

• Surgery: If the drug must be stopped, stop clopidogrel, ticagrelor, or aspirin 5 days prior and prasugrel 7 days before surgery. Continue aspirin for all but the riskiest surgery.

 
TALKING POINTS, WE WANT TO SHARE WITH OUR PATIENTS:

1. Adherence is critical for all antiplatelet therapy. Triple risk of heart attack if stopped too soon.
2. Aspirin is serious medicine, do not stop without talking to your doctor.