MEDICATION

Antiplatelet drugs

Created 02/12/2021, last revision 05/11/2023

Thrombocytes (platelets)

• platelets are formed in the bone marrow from megakaryocytes. They have a round shape, irregular margins, and no nucleus
  • life span ~ 9-12 days
  • the normal range of platelet concentration is 150–450 × 10⁹ /L  (age and sex independent)
  • 2/3 of platelets are in the circulation, 1/3 in the spleen
  • a drop in platelet count below the physiological limit is referred to as thrombocytopenia, and a rise as thrombocytosis
  • platelets contain three types of granules
    • alpha granules (von Willebrand factor-vWF, platelet factor 4, P-selectin, PDGF, fibrinogen, B-thromboglobulin, factors V and XIII)
    • dense (delta) granules (ADP, ATP, Ca2+, serotonin)
    • gamma granules (with lysosomal enzymes)

• platelets play a crucial role in the process of atherothrombosis, which contributes to a significant proportion of ischemic events (including coronary artery disease, cerebrovascular accidents, and peripheral arterial disease)
  • long-term exposure to risk factors leads to pathological changes in the arterial wall, the most significant of which is atherosclerotic involvement
  • plaque erosion or rupture stimulates platelets to aggregate, which leads  to a thrombus formation
  • thrombi can lead to vessel occlusion or be a source of embolization to peripheral branches (thromboembolism)
• antiplatelet drugs are an integral part of the primary and secondary cardiovascular prevention

Overview of antiplatelet agents, mechanism of action

• to achieve an effective blockade of primary hemostasis, over 70% of platelets need to be inhibited
• discontinuation of medication after long-term use is (especially in secondary prevention) associated with an increased risk of CV events – 1.35% per year. Thus, 1 in 74 patients will have a CV event within a year after discontinuing the medication [Sundström,2017]
• adherence to antiplatelet treatment in the absence of major surgery or bleeding is an important treatment goal

Inhibitors of cyclooxygenase

• aspirin irreversibly blocks the enzyme cyclooxygenase-1 (COX-1) inside the platelets
• it represents the cornerstone of antiplatelet therapy
  • many studies have confirmed its effect
  • compared to placebo, ASA leads to an annual absolute risk reduction (ARR) of recurrent cerebral infarction/death of about 1-2 % (number needed to treat – NNT 100) ( SALT, ESPS2)

• the recommended daily dose is 50 – 325 mg
  • higher doses yield no benefit; they only increase the risk of side effects
• low doses (30-80 mg) have a cumulative effect, and TXA2 production is maximally reduced on days 4-5
• antiplatelet effect (COX1 inhibition) can be achieved with a dose as low as 30 mg; higher doses are needed to inhibit COX2 (anti-inflammatory and analgesic effect)
• platelets cannot synthesize COX, so the effect of the drug lasts for the platelet lifetime (8-11 days)
• platelet activation can continue through other pathways
• the antiplatelet effect of aspirin is not the same in all patients; its mediated inhibition of platelet aggregation is affected by inter- and intra-individual variability. Some patients are aspirin-resistant or develop this resistance during treatment (up to 40%)

• the most common side effects:
  • GI bleeding (up to 55% higher than placebo); PPIs are recommended (there is a fixed combination of ASA+ omeprazole – YOSPRALA → see here
    • peptic ulcer with or without a history of bleeding, concomitant anticoagulation, or dual antiplatelet therapy (DAPT)
    • age :> 60 years, history of corticosteroid use, dyspepsia, or GE reflux
  • increased risk of intracerebral hemorrhage, especially with dual antiplatelet therapy and when other factors are combined
  • in the WARSS trial, the risk of major bleeding with ASA use was about 1.5%/year (with warfarin with INR 1.4-2.8) was 2.22%/year – HR 1.45, p=0.1)
  • according to a study of nearly 186,000 patients on ASA (compared to the same number of patients without ASA), ASA use was associated with a 55% increase in the risk of ICH. Which is more than initially expected. The median follow-up time was 5.7 years. The incidence of major bleeding was 5.58/1000 patients/year (ASA) vs. 3.6 (no ASA) – IRR 1.55  [JAMA 2012]

• the combination of aspirin 50 mg + controlled-release dipyridamole 200mg (ASA+DP) given twice daily is more effective than ASA alone (ARR 1.5%/year)
  • ESPS2 (The European Stroke Prevention Study, 1996) – the absolute annual risk reduction of ASA+DP compared to ASA is 1.5% (NNT/year 66)
  • ESPRIT (European/Australasian Stroke Prevention in Reversible Ischaemia Trial, 2005) – annual absolute risk reduction of ASA+DP vs. ASA is 1%
• headache was a common problem with ASA+DP ( especially when starting treatment)

Inhibitors of P2Y receptors

• membrane ADP receptors-blocker
  
• dose: 2 x 250 mg
• the onset of action of ticlopidine is gradual (within 6 h), reaching a maximum in approximately 6 days and persisting for 4-10 days after discontinuation
• efficacy of ticlopidine has been demonstrated in the CATS and TASS trials
  • the CATS  (Canadian American Ticlopidine Study) demonstrated a 6.5% absolute risk reduction in cerebral infarction over 2 years compared to placebo (10.1% vs. 16.7%), NNT/year was 30
  • the TASS ( Ticlopidine Aspirin Stroke Study) study published in 1993 showed a 2.6% reduction in absolute risk of fatal and non-fatal MI with ticlopidine compared to Anopyrin (11.2 vs. 13.8%). The mean follow-up time was 2.3 years, NNT/year was 90.
• there is a lower resistance incidence with ticlopidine compared to clopidogrel
  
• adverse events:  neutropenia (severe in approximately 1% of cases) and skin rash and diarrhea (severe in 2% of patients each); all reversible
  • perform a regular check of blood count during the first 3 months of treatment (first month each week, then every 14 days)

• non-thienopyridine reversible ADP P2Y₁₂ receptor blocker
• the advantage is the possibility of parenteral administration ensuring a rapid onset and short duration of action [Angiolillo, 2012]
• available in peroral and parenteral form
• used so far only in cardiology

• a non-thienopyridine ADP P2Y₁₂ receptor antagonist with direct and reversible action
• it has the advantage of a rapid onset of action ( within minutes), but it has a short half-life (5 minutes); therefore, continuous parenteral administration is required, and use is limited to the bridging treatment of ACS
  • pre-treatment platelet aggregation levels are achieved within 30–60 minutes

Others

• acts through selective inhibition of PDE type III
• although it has an antiplatelet effect, it must be given in combination with aspirin or clopidogrel in patients with intermittent claudication due to PAD
• in Asian countries, cilostazol has been used in addition to dual antiplatelet therapy in patients receiving coronary stents and as an alternative to aspirin in patients with ischemic stroke (↓ risk of bleeding)
• side effects: headache and diarrhea