Whether the association between platelet count (PC) and thrombotic and bleeding risk is independent of or varies by residual platelet reactivity to antiplatelet therapies is unclear. We sought to ...investigate the independent and combined effects of PC and platelet reactivity on thrombotic and bleeding risk after coronary artery implantation of drug-eluting stents (DES). Patients enrolled in the prospective, multicenter Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents study were stratified by PC tertiles. The study cohort comprised 8,402 patients. By linear regression analysis, lower PC was strongly and independently associated with higher platelet reactive units (PRUs) on clopidogrel. After multivariable adjustment (including PRU and aspirin reactive units), high, but not low, PC tertile was independently associated with higher risk of thrombotic complications, including spontaneous myocardial infarction and stent thrombosis. Although no independent association was observed between PC tertiles and hemorrhagic risk, both high and low PC tertiles were associated with increased risk for all-cause mortality. After stratification of PC tertiles by tertiles of PRUs, the crude risk of thrombotic complications was highest in patients in the high PC and high PRU tertiles. By multivariable adjustment, PRU increases were uniformly associated with higher risk of thrombotic events across PC tertiles, without evidence of interaction. In conclusion, higher PCs and higher PRUs act independently and synergistically in determining thrombotic risk. Alongside PRU, PCs could be a simple hematological parameter to consider for risk stratification and in tailoring duration and potency of pharmacologic platelet inhibition after DES implantation.
Abstract We sought to examine the relationship between various degrees of renal function and coronary plaque morphology by grayscale and virtual histology (VH) intravascular ultrasound (IVUS). ...ADAPT-DES was a prospective, multicenter registry of 8,582 consecutive patients treated using coronary drug-eluting stents with a pre-specified grayscale and VH-IVUS substudy. A lesion-level analysis of study participants was performed by comparing IVUS parameters of culprit and non-culprit lesions across tertiles of estimated creatinine clearance (CrCl). Pre-intervention IVUS imaging of 762 patients identified 898 culprit and 752 non-culprit native coronary artery lesions. Patients in the lowest CrCl tertile were older, more often female, and more often presented with stable angina. Compared to the middle and upper tertiles, the lowest tertile was significantly associated with culprit lesion smaller mean external elastic membrane cross-sectional area (CSA) (12.9 mm3 /mm vs. 14.2 mm3 /mm vs 14.9 mm3 /mm, p<0.0001), smaller mean lumen CSA (5.5 mm3 /mm vs 5.8 mm3 /mm vs 6.1 mm3 /mm, p=0.002), and more dense calcium volume (11.5% vs 10.2% vs 9.7%, p=0.02). Similar trends were found in the non-culprit lesions. Plaque rupture was least common in patients in the lowest tertile. On multivariable analysis, independent predictors of greater dense calcium volume were lower CrCl, hyperlipidemia, female sex, and presentation without ST-segment elevation myocardial infarction. In conclusion, in the present large-scale IVUS study diminishing renal function was associated with increased coronary calcification and decreased coronary vessel and lumen sizes, with a graded response according to the reduction in CrCl. In addition, these patients were more likely to present with stable angina versus patients with normal renal function who were more likely to present with an acute coronary syndrome.
Abstract Objectives The aim of this study was to evaluate the prevalence and long-term clinical impact of tissue protrusion (TP) after stent implantation. Background Stent implantation may be ...associated with tissue (plaque or thrombus) protrusion, especially in unstable lesions, but its clinical impact is unknown. Methods ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) was a prospective multicenter study of 8,663 patients undergoing percutaneous coronary intervention (PCI) using drug-eluting stents. In a pre-specified intravascular ultrasound (IVUS) substudy, 2,072 patients with 2,446 culprit lesions underwent post-PCI IVUS (among whom some also underwent pre-PCI IVUS) and were classified according to the presence or absence of post-stent TP. Results After PCI, 34.3% of lesions displayed TP on IVUS. Median maximum TP was 0.7 mm2 (interquartile range: 0.5 to 1.2 mm2 ) in area and 3.0 mm (interquartile range: 1.4 to 6.7 mm) in length. Patients with TP more often presented with ST-segment elevation myocardial infarction or non–ST-segment elevation myocardial infarction but less often with unstable angina or stable ischemic heart disease. In 893 culprit lesions that were also examined pre-PCI, TP was associated with larger reference luminal area, greater plaque burden, and more plaque ruptures, attenuated plaque, and virtual histology thin-cap fibroatheromas. Because a larger stent or post-dilation balloon was used, post-PCI luminal area was significantly larger in lesions with versus without TP. At 2-year follow-up, there was less clinically driven target lesion revascularization in lesions with TP and no significant difference in major adverse cardiac events (defined as cardiac death, myocardial infarction, or stent thrombosis) in patients with versus without TP. Conclusions IVUS-detected TP after drug-eluting stent implantation was not associated with worse long-term clinical outcomes, in part because of greater stent expansion in lesions with TP.
Abstract Objectives 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. Background These events have been strongly associated with subsequent death. Methods 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. Results 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). Conclusions 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.
Abstract Objectives This study evaluated the relationship between platelet reactivity and plaque morphology using grayscale and radiofrequency intravascular ultrasound (IVUS) virtual histology (VH). ...Background Recent studies have reported that high on-treatment platelet reactivity (HPR) is associated with higher plaque volume and the presence of multivessel disease; however, the association between HPR and plaque morphology has not been evaluated. Methods The ADAPT-DES (Dual AntiPlatelet Therapy With Drug Eluting Stents) intravascular ultrasound substudy was a prospective, multicenter, observational study of 8,582 patients undergoing percutaneous coronary intervention with drug-eluting stents in whom platelet reactivity on clopidogrel was assessed routinely. The current analysis included 909 culprit lesions from 773 patients with pre-intervention grayscale IVUS and IVUS-VH. HPR was defined as platelet reactivity >208 P2Y12 reaction unit in point-of-care P2Y12 testing by the VerifyNow assay, measured during steady-state platelet inhibition in patients receiving an antiplatelet agent. Results HPR was associated with 3-vessel coronary artery disease (31.0% vs. 24.4%; p = 0.04). The incidence of fibroatheroma was higher in patients with HPR than those without HPR (77.1% vs. 68.9%; p = 0.01). The HPR group had larger percent plaque and media volume (plaque and media/external elastic membrane volume: 58.1% 95% confidence interval (CI): 57.1% to 59.0% vs. 56.6% 95% CI: 55.8% to 57.5%; p = 0.03) and plaque burden at the minimum lumen site (76.7% 95% CI: 75.7% to 77.8% vs. 75.0% 95% CI: 74.0% to 76.0%; p = 0.02). Despite a similar prevalence of attenuated plaque, patients with HPR had longer culprit lesion attenuated plaque length (8.0 95% CI: 7.0 to 9.1 mm vs. 6.5 95% CI: 5.9 to 7.1 mm; p = 0.01). On multivariate analysis, the presence of angiographic calcium (odds ratio OR: 1.85: 95% CI: 1.33 to 2.56; p = 0.0002) and HPR (OR: 1.45; 95% CI: 1.05 to 2.01; p = 0.02) were independent predictors for a culprit lesion fibroatheroma. Conclusions HPR was associated with increased culprit lesion atherosclerotic burden and adverse plaque morphology among patients undergoing percutaneous coronary intervention. Platelet reactivity might be associated with not only blood clot formation, but also severity of atherosclerosis. (Assessment of Dual AntiPlatelet Therapy With Drug Eluting Stents ADAPT-DES; NCT00638794 )
Abstract Objectives 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. Background 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. Methods 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). Results 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. Conclusions 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 )
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