Letter to the Editors-in-Chief

Identification, Evaluation and Treatment of Prasugrel Low-Response after Coronary Stent Implantation – A Preliminary Study

The REAC-TAVI (Assessment of platelet REACtivity after Transcatheter Aortic Valve Implantation) trial enrolled patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) pre-treated with aspirin + clopidogrel, aimed to compare the efficacy of clopidogrel and ticagrelor in suppressing high platelet reactivity (HPR) after TAVI.

Current recommendations support short-term use of aspirin + clopidogrel for patients with severe AS undergoing TAVR despite the lack of compelling evidence.

This was a prospective, randomized, multicenter investigation. Platelet reactivity was measured at 6 different time points with the VerifyNow assay (Accriva Diagnostics, San Diego, California). HPR was defined as (P2Y₁₂ reaction units (PRU) ≥208. Patients with HPR before TAVR were randomized to either aspirin + ticagrelor or aspirin + clopidogrel for 3 months. Patients without HPR continued with aspirin + clopidogrel (registry cohort). The primary endpoint was non-HPR status (PRU <208) in ≥70% of patients treated with ticagrelor at 90 days post-TAVR.

A total of 68 patients were included. Of these, 48 (71%) had HPR (PRU 273 ± 09) and were randomized to aspirin + ticagrelor (n = 24, PRU 277 ± 08) or continued with aspirin + clopidogrel (n = 24, PRU 269 ± 49). The remaining 20 patients (29%) without HPR (PRU 133 ± 12) were included in the registry. Overall, platelet reactivity across all the study time points after TAVR was lower in patients randomized to ticagrelor compared with those treated with clopidogrel, including those enrolled in the registry (p < 0.001). The primary endpoint was achieved in 100% of patients with ticagrelor compared with 21% with clopidogrel (p < 0.001). Interestingly, 33% of clopidogrel responder patients at baseline developed HPR status during the first month after TAVR.

HPR to clopidogrel is present in a considerable number of patients with AS undergoing TAVR. Ticagrelor achieves a better and faster effect, providing sustained suppression of HPR to these patients. (Platelet Reactivity After TAVI: A Multicenter Pilot Study [REAC-TAVI]; NCT02224066)

High on-treatment platelet reactivity (HPR) under clopidogrel treatment is frequently observed in hemodialysis (HD) patients. In such patients, 10 mg of prasugrel has reportedly inhibited platelet reactivity more adequately compared with 75 mg of clopidogrel. However, the efficacy of 3.75 mg prasugrel in Japanese HD patients is largely unknown.

A total of 41 Japanese coronary artery disease patients under HD who received aspirin and clopidogrel were enrolled. Clopidogrel was switched to 3.75 mg prasugrel. At day 14, prasugrel was switched to clopidogrel. Platelet reactivity was measured using VerifyNow assay (Accumetrics, San Diego, CA, USA) at baseline, day 14, and day 28. VerifyNow P2Y12 reaction units (PRU) >208 was defined as HPR.

The PRU level on prasugrel therapy was significantly lower than that on clopidogrel therapy before switching (219.1 ± 62.3 PRU vs. 238.2 ± 68.0 PRU, p = 0.02). Although the prevalence of HPR was numerically lower on prasugrel therapy compared with clopidogrel therapy before and after switching, the differences did not reach a statistical significance (57.6% vs. 75.7% vs. 74.2%, p = 0.13). Even under prasugrel treatment, more than half of patients showed HPR.

Although low-dose prasugrel had somewhat better antiplatelet effect than clopidogrel, it could not significantly improve the prevalence of HPR in Japanese HD patients. Higher doses of prasugrel might be needed to achieve adequate platelet inhibition in this high thrombotic risk population.

High residual platelet reactivity (HRPR) in patients taking dual antiplatelet therapy (DAPT) is closely associated with serious ischaemic events, particularly in-stent thrombosis. Literature reports many cases of patients taking the combination of acetylsalicylic acid and clopidogrel with early in-stent thrombosis and the detection of high residual platelet reactivity, but cases in patients using a combination of new antiplatelet drugs are rare. The following case report presents the case of a patient with early in-stent thrombosis in whom HRPR was detected while he was on prasugrel therapy and describes the subsequent management of the complication.

Clopidogrel resistance is associated with stent thrombosis. Prasugrel achieves greater platelet inhibition with less variability among patients than does clopidogrel. Thus, a patient who had stent thrombosis due to clopidogrel resistance may receive prasugrel to prevent repeated episodes of stent thrombosis. This case report describes a case of repetitive stent thrombosis in which resistance not only to clopidogrel, but also to prasugrel, was observed.

<Learning objective: In the face of clopidogrel resistance, prescribing prasugrel may be an acceptable treatment option. However, cross-unresponsiveness may be observed between clopidogrel and prasugrel. Thus, platelet function assay should be performed in patients with stent thrombosis, even when clopidogrel is replaced with prasugrel.>

The study aimed to compare the antiplatelet action of ticagrelor with prasugrel in acute coronary syndrome (ACS) patients with high on-treatment platelet reactivity (HTPR) while on clopidogrel after percutaneous coronary intervention (PCI).

Newer P2Y12 inhibitors like prasugrel and ticagrelor provide stronger platelet inhibition compared with clopidogrel. Both agents are efficacious in patients with HTPR while on clopidogrel, but direct comparison between them has not yet been reported.

In a prospective, single-center, single-blind study, 44 (of 139 screened, 31.7%) ACS patients with HTPR while on clopidogrel 24 h post-PCI were randomized to either ticagrelor 90 mg twice daily or prasugrel 10 mg once daily for 15 days with a crossover directly to the alternate treatment for another 15 days. HTPR was defined as platelet reactivity units (PRU) ≥235 as assessed by the VerifyNow P2Y12 function assay.

The primary endpoint of platelet reactivity at the end of the 2 treatment periods was lower for ticagrelor (32.9 PRU, 95% confidence interval [CI]: 18.7 to 47.2) compared with prasugrel (101.3 PRU, 95% CI: 86.8 to 115.7) with a least squares mean difference of –68.3 PRU (95% CI: –88.6 to –48.1; p < 0.001). The secondary endpoint of HTPR rate was 0% for ticagrelor and 2.4% for prasugrel (1 of 42, p = 0.5). No patient exhibited a major bleeding event at either treatment group.

In patients with ACS exhibiting HTPR while on clopidogrel 24 h post-PCI, ticagrelor produces a significantly higher platelet inhibition compared with prasugrel. (Ticagrelor Versus Prasugrel in Acute Coronary Syndromes After Percutaneous Coronary Intervention; NCT01360437)