Very-low-dose twice-daily aspirin maintains platelet inhibition and improves haemostasis during dual-antiplatelet therapy for acute coronary syndrome

William A E Parker, Rachel C Orme, Jessica Hanson, Hannah M Stokes, Claire M Bridge, Patricia A Shaw, Wael Sumaya, Kirstie Thorneycroft, Giovanna Petrucci, Benedetta Porro, Heather M Judge, Ramzi A Ajjan, Bianca Rocca, Robert F Storey, William A E Parker, Rachel C Orme, Jessica Hanson, Hannah M Stokes, Claire M Bridge, Patricia A Shaw, Wael Sumaya, Kirstie Thorneycroft, Giovanna Petrucci, Benedetta Porro, Heather M Judge, Ramzi A Ajjan, Bianca Rocca, Robert F Storey

Abstract

Higher aspirin doses may be inferior in ticagrelor-treated acute coronary syndrome (ACS) patients and reducing bleeding risk whilst maintaining antithrombotic benefits could improve outcomes. We characterized the pharmacodynamics of a novel dual-antiplatelet-therapy regimen consisting of very-low-dose twice-daily (BD) aspirin with standard-dose ticagrelor. A total of 20 ticagrelor-treated ACS patients entered a randomized crossover to take aspirin 20 mg BD (12-hourly) during one 14-day period and 75 mg once-daily (OD) in the other. After 14 days of treatment, serum thromboxane (TX)B2 and light-transmittance aggregometry were assessed pre- and 2 h post-morning-dose, bleeding time was measured post-dose, and TXA2 and prostacyclin stable metabolites were measured in urine collected 2 h post-morning-dose. Data are expressed as mean ± SD. After 14 days treatment, serum TXB2 levels were significantly greater 2 h post-dosing with aspirin 20 mg BD vs. 75 mg OD (3.0 ± 3.6 ng/mL vs. 0.8 ± 1.9 ng/mL; p = 0.018) whereas pre-dosing levels were not significantly different (3.5 ± 4.1 ng/mL vs. 2.5 ± 3.1 ng/mL, p = 0.23). 1-mmol/L arachidonic acid-induced platelet aggregation was similarly inhibited by both regimens pre-dose (8.5 ± 14.3% vs. 5.1 ± 3.6%, p = 0.24) and post-dose (8.7 ± 14.2% vs. 6.6 ± 5.3%; p = 0.41). Post-dose bleeding time was shorter with 20 mg BD (680 ± 306 s vs. 834 ± 386 s, p = 0.02). Urinary prostacyclin and TX metabolite excretion were not significantly different. In conclusion, compared to aspirin 75 mg OD, aspirin 20 mg BD provided consistent inhibition of platelet TXA2 release and aggregation, and improved post-dose hemostasis, in ticagrelor-treated ACS patients. Further studies are warranted to assess whether this regimen improves the balance of clinical efficacy and safety.

Keywords: Aspirin; P2Y inhibitors; bleeding; thromboxane; ticagrelor.

Figures

Figure 1.
Figure 1.
Overall design of the WILL lOWer dose aspirin be more effective in ACS? (WILLOW ACS) study. ACS, acute coronary syndrome; BD, twice daily; mg, milligrams; OD, once daily; R, point of randomization.
Figure 2.
Figure 2.
Serum TXB2 (a) and bleeding time (b) in ACS patients receiving two regimens of aspirin and ticagrelor in the WILLOW ACS study. Bars represent mean + SD. Dots and lines represent paired values for the individual participants. p values shown were generated by paired t-tests between the groups (see text and tables for further details). BD, twice-daily; OD, once-daily s, seconds; sTXB2, serum thromboxane B2. the groups (see text and tables for further details). Scale on the y-axis in Figure 2(a) is logarithmic. BD, twice-daily; OD, once-daily s, seconds; TXB2, thromboxane B2.
Figure 3.
Figure 3.
Maximum platelet aggregation responses to arachidonic acid, adenosine diphosphate and collagen assessed by light transmittance aggregometry pre- and post-aspirin dose at the end of each treatment period in the WILLOW ACS study. Bars indicate mean + SD. p values were generated using prespecified paired t-tests. AA, arachidonic acid; ADP, adenosine diphosphate; BD, twice-daily; OD, once-daily.
Figure 4.
Figure 4.
Urinary levels of TX metabolite, PGI2 metabolite 8-iso-PGF2α measured at the end of each treatment period. Bars represent mean + SD. Dots and lines represent paired values for the individual participants. p values shown were generated by paired t-tests between the groups. Scale on the y-axis is logarithmic. 8-iso-PGF2α, 8-iso prostaglandin F2α; BD, twice- daily; PGI-M, prostacyclin metabolite; OD, once-daily; TxM, thromboxane metabolite.
Figure 5.
Figure 5.
Conceptual figure summarizing the anticipated profiles of COX-1 inhibition and hemostasis provided by maintenance aspirin doses of 75 mg OD or 20 mg BD in combination with ticagrelor 90 mg BD, during steady-state. Figure for illustrative purposes only, scale on the y-axis is arbitrary. Dashed line represents effects on COX-1 and hemostasis at steady-state trough levels. BD, twice-daily; COX-1, cyclo-oxygenase 1; mg, milligrams; OD, once-daily.

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