In this study, we identified an optimal therapeutic window of 25.5% − 37.4% for PLADP as determined by LTA for patients underwent PCI and on the treatment of regular-dose aspirin and clopidogrel, and approximately one third (29.6%) of the patients meet this therapeutic window. Patients inside the window presented significantly lower risk of NACE than those outside the window during 12-month follow-up.
Several studies have tried to identify a threshold of PR that could stratify patients at risk of ischemic events. Bliden et al.  found that HOPR (defined as PLADP ≥50% measured by LTA with ADP concentration of 5 µmol/L) was the only variable being significantly related to ischemic events after adjusting parameters of hypertension, diabetes and use of calcium channel inhibitors. Gurbel et al.  demonstrated that HOPR (defined as PLADP ≥46% measured by LTA with ADP concentration of 5 µmol/L) was an independent risk factor for ischemic events within 2 years of non-emergent PCI (OR = 3.9, p < 0.001).
The cutoff value of PLADP in our study is 37.5%, which is lower than the previous study. However, as demonstrated by the GRAVITAS trial, when HOPR was defined as ≥ 230 PRU by VerifyNow P2Y12 test, high-dose clopidogrel compared with standard-dose clopidogrel did not reduce the incidence of major adverse cardiovascular events, while the post-hoc analysis found that the achievement of a PRU < 208 was associated with significantly improved clinical outcomes. Consistent with the GRAVITAS trial, our result suggests that a lower cutoff value of PLADP might bring more low responders to the intensified anti-platelet treatment and consequently reduce more ischemic events.
In addition to recurrent ischemic events, the prognostic importance of bleeding complications following PCI has also been established. ADAPT-DES trial showed that HOPR (defined by > 208 PRU, by VerifyNow P2Y12 test) was inversely related to TIMI major bleeding (adjusted HR: 0.73, 95% CI: 0.61 to 0.89, p = 0.002). Studies suggested a possible link between LOPR and bleeding [7–9, 18–23]. With the LTA method, Tsukahara et al found that high-responsiveness was the independent predictor of major bleeding in patients receiving drug-eluting stents and treated with thienopyridine. Parodi et al reported that LOPR (PLADP<40%, 10µmol/L ADP, LTA assay) were the independent predictor of bleeding events. Consistent with previous studies, we confirmed the predictive value of PR on the occurrence of bleeding events after PCI as measured with the LTA assay, and we suggested a cutoff value of PLADP<25.5% to predict the bleeding events.
The optimal therapeutic window of PLADP is uncertain, Campo and Mangiacapra et al have reported two therapeutic windows for PR measured with the VerifyNow P2Y12 assay. However, in Campo’s study, they reported all clinical events (ischemic and bleeding) after 1 month and up to 1 year of follow-up. Patients with adverse events during the first month were excluded. In Mangiacapra’s study, only short-term outcome of 1-month clinical events were analyzed. By contrast, using the two thresholds for ischemic and bleeding events, we found an optimal therapeutic window for PLADP by LTA assay, ranging from 25.5–37.4%, which was associated with the lowest 1-year incidence of NACE. To the best of our knowledge, our study was the first that use LTA method to demonstrate an optimal therapeutic window for PLADP regarding the 1-year clinical outcome.
Our study has important clinical implications. According to the results, post-PCI evaluation of PR carries important prognostic information, and the antiplatelet treatment should be guided referring to optimal therapeutic window of PR instead of single cutoff value. In particular, for patients with HOPR and higher ischemic risk, more aggressive antiplatelet strategies might be useful. On the other hand, for patients with LOPR and higher bleeding risk, conservative antiplatelet therapies should also be indicated until PR falls within the desired range.