Potent P2Y12 receptor inhibitor shows stronger antithrombotic effect in T2DM patients with CVD

Background

Type 2 diabetes (T2DM) patients have a high risk of CV morbidity and mortality, which is partly caused by platelet hyperreactivity [1-3]. Inhibition of the P2Y12 receptor by antiplatelet therapy has shown great clinical benefits in the prevention of secondary coronary events in CVD patients [4,5]. However, data on the effects in T2DM patients are limited and usually obtained from subgroup analyses [6]. Available studies show that in addition to increased platelet reactivity, patients respond less to antiplatelet therapy than non-diabetic patients. The PLATO trial demonstrated a faster and significant reduction in CV events in ACS patients treated with ticagrelor compared to clopidogrel. Although results in the diabetic subgroup were similar, no significance was detected [7].

A randomized, cross-over, open-label, 2-treatment trial in T2DM patients with stable CVD was conducted. Patients (n=20) were treated with both therapies, consisting of either ticagrelor or clopidogrel, with a 2-week washout period in between, and randomized to one of the two treatment sequences. Patients received a loading-dose plus one week of daily therapy of each treatment. Antithrombotic effects were measured in an ex vivo model in which non-anticoagulated blood is perfused over a thrombogenic substrate. The difference between thrombus areas before and after the intervention is a measure for the antithrombotic effect of the study treatment. Platelet function was assessed with multiple electrode aggregometry, in which adenosine diphosphate triggers platelet aggregation via the P2Y12-receptor pathway. Moreover, VerifyNow was used to assess aggregation in whole blood treated with the P2Y12-receptor inhibitors, using light transmittance.

Main results

• Treatment with clopidogrel resulted in a reduction of 16%, 20% and 17% of thrombus size at high shear at 2 hours, 6 hours and 7 days, with only a significant reduction for the 6 hour timepoint. In contrast, treatment with ticagrelor resulted in a significantly reduced thrombus size at each timepoint (33%, 40% and 31%, respectively). Also, a significant difference in thrombus size was found between treatment with ticagrelor and clopidogrel at the 6 hour timepoint.
• A similar pattern was observed for thrombus formation at low shear, although reductions in thrombus size were smaller, since platelets do not play a major role under these conditions.
• Multiple electrode aggregation showed reductions of 46%, 56% and 54% with clopidogrel treatment at 2 hours, 6 hours, and 7 days, respectively. After treatment with ticagrelor, reductions in aggregation from baseline were larger (79%, 79% and 15%, respectively). At each timepoint, platelet aggregation with ticagrelor treatment was significantly lower than the aggregation with clopidogrel.
• Platelet aggregation as measured with VerifyNow showed a similar pattern with a more profound difference between treatment with ticagrelor and clopidogrel, with lower P2Y12 reaction units (PRU) for ticagrelor (42 vs 220 at 2 hours, 23 vs 189 at 6 hours, and 41 vs 177 at 7 days).

Conclusion

References

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