Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • Potential platelet related mechanisms that

    2021-11-25

    Potential platelet-related mechanisms that might explain an augmented risk of MI in dabigatran treated patients have been investigated: Enhanced platelet reactivity is known to be associated with the risk of MI (Mangiacapra et al., 2018) and catalytically active thrombin is a potent stimulus to induce platelet aggregation. Therefore, analyzing the interaction of dabigatran and platelet reactivity seems reasonable. It was recently shown that dabigatran enhanced platelet adhesion in an in-vitro flow chamber model and led to increased thrombus formation on human atherosclerotic plaque material (Petzold et al., 2016). These pro-thrombotic effects were shown to depend on altered thrombin glycoprotein (GP) Ibα interaction leading to an augmented GPIbα signaling downstream of von Willebrand factor binding (Petzold et al., 2016). Interestingly, this mechanism was independent of the catalytic activity of thrombin with subsequent induction of plasmatic coagulation (Franchi et al., 2016; Petzold et al., 2016). Furthermore, dabigatran enhanced thrombin-induced platelet aggregation measured by light-transmittance aggregometry, while there was no influence on aggregation induced by other agonists like adenosine diphosphate (ADP), collagen, or arachidonic ghrelin receptor antagonist respectively (Achilles et al., 2017). This effect was measurable after a single dose of dabigatran (Achilles et al., 2017). Repeated dosing led to additional increase of platelet reactivity (Olivier et al., 2016). These pro-thrombotic effects of dabigatran were found to be dose-dependent with higher platelet reactivity in 150 mg dabigatran b.i.d. as compared to 110 mg b.i.d. treated patients (Olivier et al., 2016). The underlying mechanism is an increased surface expression measured by fluorescence activated cell sorting analysis of platelet protease activated receptor (PAR)-1 and PAR-4 on platelets (Achilles et al., 2017). An in-vitro study found that dabigatran leads to an acute inhibition of thrombin-induced PAR-1 cleavage, activation and internalization in a dose dependent manner (Chen et al., 2015). Furthermore, it could be shown that prolonged exposure to inactivated thrombin by dabigatran resulted in increased PAR-1- surface expression (Chen et al., 2015). In summary, these studies identified potential pro-thrombotic mechanisms that might contribute to the increased frequency of MI in dabigatran treated patients seen in clinical trials (Fig. 1).
    Factor-Xa-inhibitors and risk of myocardial infarction In contrast to dabigatran, the factor Xa-inhibitor landmark trials revealed a numerical reduction of MI (Giugliano et al., 2013; Granger et al., 2011; Patel et al., 2011). (Table 1) A meta-analysis found a significantly reduced risk of MI and cardiovascular mortality under rivaroxaban tested against different controls (Chatterjee et al., 2013). Along this line, the results of PIONEER AF-PCI, which investigated rivaroxaban in combination with antiplatelet therapy in patients with AF undergoing PCI, found a similar trend: Again a numerical decrease of MI was observed in rivaroxaban treated patients compared to VKA (Gibson et al., 2016). In this context, the trials investigating apixaban and edoxaban with antiplatelet therapy in patients after PCI are awaited eagerly (AUGUSTUS, ENTRUST-AF-PCI). Beside its role in AF, factor Xa inhibition has previously been well investigated in patients with coronary artery disease without AF. Rivaroxaban in conjunction with antiplatelet therapy reduced the rate of death from cardiovascular causes, myocardial infarction and stroke in patients after myocardial infarction in ATLAS ACS 2-TIMI (Mega et al., 2012). Additionally, the recent COMPASS trial revealed improved cardiovascular outcome in patients with stable coronary artery disease additionally treated with rivaroxaban and low-dose aspirin (Eikelboom et al., 2017). However, these benefits did not hold true for all factor Xa inhibitors: Apixaban was unable to obtain a net clinical benefit on top of antiplatelet medication in patients after acute coronary syndrome due to an increase in major bleeding events in APPRAISE-2 (Alexander et al., 2011). However, in contrast to reduced-dose regimen in COMPASS or ATLAS-ACS (2.5 mg rivaroxaban b.i.d.), the apixaban dose used for stroke prevention due to AF was applied in APPRAISE-2 (5 mg b.i.d.) (Alexander et al., 2011). This might have contributed to the increase in major bleedings. Despite this, the rate of MI was decreased in APPRAISE-2 as well (Alexander et al., 2011).