Expert Review: Pharmacotherapy

Projected inhibition of platelet aggregation with ticagrelor twice daily vs. clopidogrel once daily based on patient adherence data (the TWICE project).

Aim of the Study
TWICE project study compared the anticipated inhibition of platelet aggregation (IPA) of ticagrelor twice-daily to clopidogrel once-daily using patients’ adherence data.

Methods
Using an electronically compiled dosing history, data of 5014 patients prescribed cardiovascular medications (primarily hypertension drugs) with once-daily (677) and twice-daily (677) regimens were gathered.
The IPA level for each patient dosing history was simulated for a period of 30 days after a loading dose, based upon the onset/offset IPA characteristics (20 μmol/L ADP; final extent) of the loading and maintenance dose of both ticagrelor and clopidogrel and upon the independently retrieved twice-daily and once-daily dosing histories.

Results
The study found that missing one dose was frequent in both regimen groups. Only 25.7% of patients in the twice-day regimen group missed two consecutive doses. Therefore, 1-day dose-free interval occurred in 25.7% in this group compared with 47% of once-daily regimen (1 missing dose). Nevertheless, the IPA of fully adherent clopidogrel (once-daily) patients was not lowered below the 24h trough levels by missing a single dose of ticagrelor (twice-daily). Moreover, comparable IPA levels were obtained on missing 1 day dose of ticagrelor twice-daily to that on missing 1 day dose of clopidogrel once-daily
Significantly higher mean IPA-averages remained for ticagrelor twice-daily (81%) as that for clopidogrel once-daily (55%; p<0.001), which were revealed by the simulations based on observed patient adherence over time. . Conclusion The projected level of platelet inhibition remained higher for ticagrelor twice daily than clopidogrel once daily, mainly due to the higher IPA level achieved with ticagrelor and the relatively low likelihood of missing two consecutive twice daily doses. This modelling and simulation study suggests a therapeutic benefit of ticagrelor over clopidogrel when taking into account the most common dosing omissionsClinical Impact: Model-based simulations using observed patient dosing histories showed that both average and trough IPA levels remained significantly higher for ticagrelor than for clopidogrel, despite somewhat lower percentages of prescribed doses taken with twice-daily ticagrelor than with once-daily clopidogrel. Twice daily dosing regimen maintains a better continuity of drug plasma levels than once daily dosing for drugs with a half life of ~12h. There is superior platelet IPA with twice-daily administered Ticagrelor compared with once daily clopidogrel. The clinical benefits of twice-daily ticagrelor compared with once-daily clopidogrel have also been confirmed in the Platelet Inhibition and Patient Outcomes (PLATO) trial2 in patients with acute coronary syndromes, with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding. This result is consistent with the twice-daily regimen’s ability to maintain a greater degree of continuity of drug action than was achieved by the once-daily regimen, notwithstanding the fact that a higher percentage of prescribed doses were taken with the once-daily than with the once-daily regimen. Nonetheless, there are other factors that may have contributed to the observed differences between ticagrelor and clopidogrel , such as the fact that both drugs are not identical in their action. While once-daily dosing may be seen as an option to simplify the dosing regimen and increase patient adherence, in fact it may require near perfect adherence to achieve its intended pharmacodynamic and clinical results, whereas the twice-daily dosing is, depending on the drug`s pharmacokinetics, more forgiving of variations in dose-timing or occasionally missed doses.Corresponding author from original paper AARDEX Ltd, Rue des Cyclistes Frontière 24, B-4600 Visé, Belgium. Tel: +32-4-374-86-35; Fax: +32-4-374-86-22; Email: bernard.vrijens@aardex.ne

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