Impact of Aspirin and Clopidogrel Hyporesponsiveness in Patients Treated With Drug-Eluting Stents: 2-Year Results of a Prospective, Multicenter Registry Study.

In this analysis of 2-year outcomes in the ADAPT-DES (Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents) study, the authors sought to examine the independent associations between platelet reactivity to both aspirin and clopidogrel and subsequent outcomes. The relationship between platelet reactivity and long-term adverse events following implantation of drug-eluting stents (DES) has been incompletely characterized. The ADAPT-DES study was a multicenter registry of patients undergoing routine platelet function testing following percutaneous coronary intervention with DES. The primary study endpoint was definite or probable stent thrombosis (ST); other endpoints were all-cause mortality, myocardial infarction, and clinically relevant bleeding. A total of 8,582 patients were enrolled between 2008 and 2010; 46.3% of patients were on dual antiplatelet therapy at 2 years without discontinuation. At 2 years, definite or probable ST occurred in 92 patients (1.07%). In patients treated with dual antiplatelet therapy continuously for 2 years, high platelet reactivity on clopidogrel was independently associated with definite or probable ST (adjusted hazard ratio [HR]: 2.16; 95% confidence interval [CI]: 1.27 to 3.67; p = 0.003), myocardial infarction (adjusted HR: 1.35; 95% CI: 1.05 to 1.74; p = 0.02), freedom from clinically relevant bleeding (adjusted HR: 0.74; 95% CI: 0.62 to 0.90; p = 0.002), and all-cause mortality (adjusted HR: 1.36; 95% CI: 1.01 to 1.85; p = 0.04). Between years 1 and 2, high platelet reactivity was not associated with the very late ST and in patients on aspirin monotherapy, aspirin hyporesponsiveness was not associated with adverse outcomes. The present study confirms the strong relationship of high platelet reactivity on clopidogrel to 2-year ischemic and bleeding outcomes after DES. The majority of stent-related events occurred within the first year.

Stuckey TD ，Kirtane AJ ，Brodie BR ，Witzenbichler B ，Litherland C ，Weisz G ，Rinaldi MJ ，Neumann FJ ，Metzger DC ，Henry TD ，Cox DA ，Duffy PL ，Mazzaferri EL Jr ，Gurbel PA ，Mehran R ，Généreux P ，Ben-Yehuda O ，Simonton CA ，Stone GW ，ADAPT-DES Investigators ... -  《-》

Sex Differences in the Clinical Impact of High Platelet Reactivity After Percutaneous Coronary Intervention With Drug-Eluting Stents: Results From the ADAPT-DES Study (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents).

Sex differences in the outcomes after percutaneous coronary intervention with drug-eluting stents and in the response to clopidogrel therapy have been reported; however, the differential risk of high platelet reactivity (HPR) on clopidogrel in women versus men is unknown. We compared 8448 patients enrolled in the ADAPT-DES study (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) according to sex and the presence/absence of HPR on clopidogrel (defined as P2Y12 reactivity units >208). Study end points were definite and probable stent thrombosis (ST), clinically relevant bleeding, all-cause mortality, myocardial infarction, and major adverse cardiac events (comprising mortality, myocardial infarction, and target lesion revascularization). HPR was more common among women (1118/2163, 51.7%) than men (2491/6285, 39.6%). HPR was associated with a roughly double risk of 1-year ST in both women and men (women with versus without HPR: 1.4% versus 0.7%; hazard ratio [HR], 2.02; 95% confidence interval [CI], 0.82-4.95; P=0.12; and men: 1.2% versus 0.5%; HR, 2.42; 95% CI, 1.36-4.30; P=0.002; Pinteraction=0.73). HPR was associated with almost half the rate of clinically relevant bleeding in women (women: HPR versus no HPR, 5.3% versus 9.8%; HR, 0.54; 95% CI, 0.40-0.74; P<0.001), whereas men had similar rates of bleeding regardless of HPR status (men: HPR versus no HPR, 5.7% versus 5.9%; HR, 0.96; 95% CI, 0.78-1.18; P=0.70; Pinteraction=0.003). In propensity-adjusted models, HPR was an independent predictor of ST and myocardial infarction in men; although both associations were nonsignificant among women, no interaction was observed in the associations between HPR and either ST or myocardial infarction. Conversely, HPR was an independent predictor of reduced bleeding only in women (women: adjusted HR, 0.58; 95% CI, 0.41-0.82; P=0.002; and men: adjusted HR, 0.83; 95% CI, 0.65-1.04; P=0.11; Pinteraction=0.01). In the current analysis, the associated risk of HPR for ST was similar in both sexes. However, HPR was associated with significantly reduced bleeding only among women. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00638794.

Yu J ，Mehran R ，Baber U ，Ooi SY ，Witzenbichler B ，Weisz G ，Rinaldi MJ ，Neumann FJ ，Metzger DC ，Henry TD ，Cox DA ，Duffy PL ，Mazzaferri EL Jr ，Brodie BR ，Stuckey TD ，Maehara A ，Xu K ，Ben-Yehuda O ，Kirtane AJ ，Stone GW ... -  《-》

Is There an Ideal Level of Platelet P2Y12-Receptor Inhibition in Patients Undergoing Percutaneous Coronary Intervention?: "Window" Analysis From the ADAPT-DES Study (Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents).

This study sought to determine whether there is an ideal level of platelet reactivity (PR) to optimize safety and efficacy within the large multicenter ADAPT-DES (Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents) study of 8,582 patients receiving successful drug-eluting stent implantation. Patients with high PR on clopidogrel have a greater incidence of adverse ischemic events after stent implantation, whereas low PR may increase bleeding. Due to limited sample size, previous studies have not been able to adjust for differences in baseline characteristics that may confound the relationship of PR and outcomes. In the ADAPT-DES study, routine platelet function testing (VerifyNow) was performed following clopidogrel loading. To characterize the independent association between PR and clinical events, patients were stratified into quintiles of P2Y12 reaction units (PRU). The PRU medians of the 5 quintiles were 57, 130, 187, 244, and 317 (most to least inhibited). There was a monotonic association between successively higher PRU quintiles and stent thrombosis, whereas for clinically relevant bleeding, the greatest risk occurred in the lowest PRU quintile, with similar risks across the 4 higher quintiles. These relationships remained significant in fully adjusted multivariable analyses (adjusted hazard ratio [HR] for stent thrombosis in Q5 versus Q1: 2.32; 95% confidence interval [CI]: 1.17 to 4.59; p = 0.02; adjusted HR for clinically relevant bleeding in Q5 versus Q1: 0.61; 95% CI: 0.47 to 0.77; p < 0.001). However, there were no significant independent associations between the level of PRU and mortality. In this large observational study, increasing PRU was associated with a monotonic increase in stent thrombosis, whereas bleeding risk was confined to the lowest PRU quintile, suggesting an optimal therapeutic window of platelet inhibition at moderately inhibited PRU. However, there was no demonstrable threshold effect for PRU and mortality in adjusted analyses, perhaps due to the offsetting impact of bleeding and ischemia across the spectrum of platelet inhibition. (Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents [ADAPT-DES]; NCT00638794).

Kirtane AJ ，Parikh PB ，Stuckey TD ，Xu K ，Witzenbichler B ，Weisz G ，Rinaldi MJ ，Neumann FJ ，Metzger DC ，Henry TD ，Cox DA ，Duffy PL ，Brodie BR ，Mazzaferri EL Jr ，Parvataneni R ，Maehara A ，Généreux P ，Mehran R ，Stone GW ... -  《-》

Platelet Reactivity and Clinical Outcomes After Coronary Artery Implantation of Drug-Eluting Stents in Subjects With Peripheral Arterial Disease: Analysis From the ADAPT-DES Study (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents).

Patients with peripheral arterial disease (PAD) have high rates of adverse cardiovascular events after percutaneous coronary intervention and may additionally have heightened platelet reactivity. This study assessed the relationship between platelet reactivity and clinical outcomes after percutaneous coronary interventions among subjects with and without PAD. ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) was a prospective, multicenter registry of patients treated with coronary drug-eluting stents. Platelet reactivity was assessed by the VerifyNow point-of-care assay; high on-treatment platelet reactivity (HPR) was defined as P2Y12 reaction units >208. A propensity-adjusted multivariable analysis was performed to determine the relationship between PAD, platelet reactivity, and subsequent adverse events (definite or probable stent thrombosis, all-cause mortality, myocardial infarction, and clinically relevant bleeding). Among 8582 patients, 10.2% had a history of PAD. Patients with PAD were older and more likely to have comorbid conditions; however, mean P2Y12 reaction units and HPR were not significantly different between PAD and no PAD groups. Patients with PAD had higher 2-year rates of all-cause mortality, myocardial infarction, stent thrombosis, and clinically relevant bleeding. Associations between HPR and adverse events were similar in PAD and no PAD groups, without evidence of interaction; however, adverse event rates were highest among subjects with both PAD and HPR. In a propensity-adjusted multivariable model, both PAD and HPR were independent predictors of myocardial infarction at 2 years. A history of PAD was associated with ischemic and bleeding outcomes 2 years after successful coronary drug-eluting stent implantation; however, these associations did not seem to be directly mediated by heightened platelet reactivity. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00638794.

Gupta R ，Kirtane AJ ，Ozan MO ，Witzenbichler B ，Rinaldi MJ ，Metzger DC ，Weisz G ，Stuckey TD ，Brodie BR ，Mehran R ，Ben-Yehuda O ，Stone GW ... -  《-》

The Impact of Timing of Ischemic and Hemorrhagic Events on Mortality After Percutaneous Coronary Intervention: The ADAPT-DES Study.

The aim of this study was to understand the impact of the timing of ischemic and hemorrhagic events after percutaneous coronary intervention (PCI) with drug-eluting stents on subsequent mortality. These events have been strongly associated with subsequent death. In the multicenter, prospective ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug Eluting Stents) study, patients at 11 clinical sites with successful PCI with drug-eluting stents underwent assessment of platelet function and were followed for 2 years. Events occurring after PCI-definite or probable stent thrombosis (ST), myocardial infarction (MI) not related to ST, and clinically relevant bleeding (CB)-were classified as early (≤30 days), late (31 to 365 days), or very late (>365 days). Mortality within 30 days of each event was estimated by Kaplan-Meier methodology. Cox regression multivariate modeling was used to analyze the relationship between each event (as a time-updated variable) and mortality over the entire study period. Among 8,582 patients, 1,060 (12.4%) had events-691 (8.1%) had CB, 294 (3.4%) had MI, and 75 (0.9%) had ST-and 7,522 (87.6%) had no events. The highest risk was associated with early ST (38.5% mortality at 30 days after the event), whereas very late MI (7.5%) and late CB (7.3%) were less dangerous. By multivariate analysis, each event was independently predictive of death, with hazard ratios of 2.4, 1.8, and 11.4, respectively (p < 0.0001). Approximately 1 in 8 patients successfully undergoing PCI with drug-eluting stents had CB, MI, or ST during the ensuing 2 years. These events are associated with an increased hazard of mortality, particularly within the first 30 days following the event, warranting efforts to prevent their occurrence.

Brener SJ ，Kirtane AJ ，Stuckey TD ，Witzenbichler B ，Rinaldi MJ ，Neumann FJ ，Metzger DC ，Henry TD ，Cox DA ，Duffy PL ，Mazzaferri EL Jr ，Mehran R ，Parvataneni R ，Brodie BR ，Stone GW ... -  《-》