Aspirin has little additional anti-platelet effect in healthy volunteers receiving prasugrel

Abstract

Background: Strong P2Y(12) blockade, as can be achieved with novel anti-platelet agents such as prasugrel, has been shown in vitro to inhibit both ADP and thromboxane A(2) -mediated pathways of platelet aggregation, calling into question the need for the concomitant use of aspirin.

Objective: The present study investigated the hypothesis that aspirin provides little additional anti-aggregatory effect in a group of healthy volunteers taking prasugrel. STUDY PARTICIPANTS/METHODS: In all, 9 males, aged 18 to 40 years, enrolled into the 21-day study. Prasugrel was loaded at 60 mg on day 1 and maintained at 10 mg until day 21. At day 8, aspirin 75 mg was introduced and the dose increased to 300 mg on day 15. On days 0, 7, 14 and 21, platelet function was assessed by aggregometry, response to treatments was determined by VerifyNow and urine samples were collected for quantification of prostanoid metabolites.

Results: At day 7, aggregation responses to a range of platelet agonists were reduced and there was only a small further inhibition of aggregation to TRAP-6, collagen and epinephrine at days 14 and 21, when aspirin was included with prasugrel. Urinary prostanoid metabolites were unaffected by prasugrel, and were reduced by the addition of aspirin, independent of dose.

Conclusions: In healthy volunteers, prasugrel produces a strong anti-aggregatory effect, which is little enhanced by the addition of aspirin. The addition of aspirin as a dual-therapy with potent P2Y(12) receptor inhibitors warrants further investigation.

Fig 1

VerifyNow™ aspirin and P2Y₁₂ cartridge reactivity. Upper panel, percent inhibition of P2Y₁₂ cartridge reactivity, normalized to baseline for values for each of nine study participants. Lower panel, Aspirin Reactivity Units (ARUs) for each of nine study participants at baseline, and study days 7, 14 and 21. ARU values < 550 indicate a response to aspirin (abnormal platelet response to arachidonic acid). In each panel, group means are indicated by a horizontal line. o.d., once daily.

Fig 2

Platelet aggregation induced by arachidonic acid (0.03–1 mm; panel A), ADP (0.1–30 μm; panel B), collagen (0.1–30 μg mL⁻¹; panel C), epinephrine (0.001–100 μm; panel D), TRAP6 (0.1–30 μm; panel E) and U46619 (0.1–30 μm; panel F) at baseline and on days 7, 14 and 21 (prasugrel, prasugrel + low aspirin and prasugrel + high aspirin, respectively). Data shown are mean ± standard error of the mean (SEM) of responses measured by 96-well plate aggregometry in citrated platelet-rich plasma (PRP) prepared from nine different individuals. All data points were analyzed by two-way anova with Bonferroni’s post test. *Represents a significant difference, P-value < 0.05, compared with baseline; ‡represents a significant difference, P-value < 0.05, between prasugrel and prasugrel + low aspirin. Symbols at the end of rows indicate a difference between all points; symbols at individual points signify particular differences.

Fig 3

Platelet production of TXA₂ induced by arachidonic acid (0.03–1 mm; panel A) and collagen (0.1–30 μg mL⁻¹; panel B) at baseline and days 7, 14 and 21 (prasugrel, prasugrel + low aspirin and prasugrel + high aspirin, respectively). Data shown are mean ± standard error of the mean (SEM) of responses collected from 96-well plate aggregometry in citrated platelet-rich plasma (PRP) prepared from nine study particpants. *Shows P < 0.05 difference from baseline by two-way anova plus Bonferroni’s post test; †Shows P < 0.05 difference between prasugrel and prasugrel + low aspirin. Symbols at the end of lines signify a difference in set; symbols at individual points signify particular differences.

Fig 4

Urinary PGI-M (panel A) and TX-M (panel B) production at days 0, 7, 14 and 21 (baseline, prasugrel, prasugrel + low aspirin and prasugrel + high aspirin, respectively). Values for urinary prostanoid metabolites (PGI-M or TX-M) are corrected against urinary creatinine concentration. Data shown are mean ± standard error of the mean (SEM) of nine study participants. *Shows P < 0.01 difference from Day 0 by one-way anova plus Bonferroni’s post test.