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, 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)
Platelet
  • 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
  • the traditional designation of antiplatelet drugs as antiaggregants is currently abandoned because of factual inaccuracy – different antiplatelet drugs affect different phases of platelet activation (not only aggregation)
  • antiplatelet therapy is not aimed at reducing the number of platelets but at influencing their function (i.e., inhibiting any of the phases of white clot formation)
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Overview of antiplatelet agents, mechanism of action

  • to achieve 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
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Inhibitors of cyclooxygenase

Acetylsalicylic acid (ANOPYRIN, GODASAL, STACYL, VASOPIRIN)
  • 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, 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), in some patients 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]
Aspirin + dipyridamole (AGGRENOX)
  • 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)
Indobufen (IBUSTRIN)
  • indications: antiplatelet therapy, e.g., in cerebrovascular and cardiac ischemic disease, peripheral vascular disease of atherosclerotic nature, venous thrombosis, disorders of fat metabolism, and diabetes
  • dosage 2 x 200 mg, dose reduction in nephropathy (according to creatinine clearance):
    • > 70 ml/min … 200 mg twice daily
    • 30-80 ml/min … 100 mg twice daily
    • <30 ml/min … 100 mg once daily
  • not stated in the AHA/ASA guidelines
  • AEs: bleeding, GIT difficulties, headache, impaired renal function, decrease in leukocytes and platelets

Inhibitors of P2Y receptors

Clopidogrel (TROMBEX, ZYLLT, EGITROMB)
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Ticlopidin (APO-TIC, TAGREN)
  • 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%). 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)
Prasugrel (EFIENT)
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A common feature of these representatives of the three generations of thienopyridine ADP receptor blockers is the irreversible inhibition of the receptor itself. Because the nucleus-free platelet can no longer synthesize another receptor, it remains dysfunctional for the whole life-time (approximately one week). This feature may be helpful – it ensures sufficient blockade of primary hemostasis even during a short interruption of treatment. In bleeding complications, on the contrary, several days persisting antiplatelet effect may be undesirable.

Ticagrelor (BRILIQUE)
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THALES

  • n=11,016 patients underwent randomization (5523 in the ticagrelor–aspirin group and 5493 in the aspirin group)
  • TIA or mild stroke (NIHSS score ≤5) of noncardioembolic etiology, patients  were not undergoing IVT or endovascular treatment
  • ASA+ticagrelor (loading dose 180 mg, then 2x 90 mg daily) vs. ASA alone (loading 300 mg, then 100 mg/d)
  • a primary-outcome event (stroke or death) within 30 days: 303 (5.5% ASA+ticagrelor) vs. 362 (6.6% – aspirin group)
  • severe bleeding: 28 (0.5%) vs 7 (0.1% aspirin group)
  • the risk of the composite of stroke or death within 30 days was lower with ticagrelor–aspirin than with aspirin alone, but the incidence of disability did not differ significantly between the two groups [Johnston, 2020]
  • effect present even in patients with NIHSS 4-5 (moderate stroke) [Wang, 2021]
  • sub-analysis showed higher efficacy in patients with ipsilateral atherosclerotic involvement (stenosis ≥ 30%) [Amarenco, 2020]
    • primary endpoint at 30 days – for stenosis 8.1% vs. 10.9% (monotherapy), NNT 34, for patients without stenosis 4.8% vs. 5.4%

SOCRATES

  • (ASA vs ticagrelor) in patients with recent stroke/TIA did not show superior efficacy of ticagrelor compared to ASA → see here
  • initial bolus of ASA 300/ticagrelor 180 mg, then ASA 100mg/ticagrelor 2x90mg
  • primary endpoint: ticagrelor 442/ 6589 patients (6.7%), ASA 497/ 6610 (7.5%), hazard ratio 0.89)
  • main secondary endpoint – ischemic stroke – 5.8% (ticagrelor) vs 6.7% (ASA), hazard ratio, 0.87)
  • no benefit of ticagrelor demonstrated in patients who were taking ASA prior to qualifying stroke
  • according to subanalysis, ticagrelor appears to be more effective than ASA in the subgroup of patients with atherosclerotic stenosis ≥ 50% (6.7 vs 9.6%) [Amarenco, 2017]

PRINCE

  • according to the PRINCE study, the combination of ASA + ticagrelor seems to be better than ASA + CLP (according to laboratory resistance tests)
  • fewer laboratory-detected resistances (12.5% vs 29.7%), 10.8% vs 35.4% in patients with dysfunctional CYP2C19 alleles
  • phase III trial is needed to assess the clinical significance
Elinogrel
  • non-thienopyridine reversible ADP P2Y12 receptor blocker
  • 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
Cangrelor (KENGREXAL)
  • 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 very 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 minute

Others

Cilostazol
  • acts by selective inhibition of PDE type III
  • although it has an antiplatelet effect, it needs to 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 agents in patients receiving coronary stents and as an alternative to aspirin in patients with ischemic stroke (↓ risk of bleeding)
  • side effects: headache and diarrhoea
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