Summary Background The relation between platelet reactivity and stent thrombosis, major bleeding, and other adverse events after coronary artery implantation of drug-eluting stents has been ...incompletely characterised. We aimed to determine the relation between platelet reactivity during dual therapy with aspirin and clopidogrel and clinical outcomes after successful coronary drug-eluting stent implantation. Methods ADAPT-DES was a prospective, multicentre registry of patients successfully treated with one or more drug-eluting stents and given aspirin and clopidogrel at 10–15 US and European hospitals. We assessed platelet reactivity in those patients after successful percutaneous coronary intervention using VerifyNow point-of-care assays, and assigned different cutoffs to define high platelet reactivity. The primary endpoint was definite or probable stent thrombosis; other endpoints were all-cause mortality, myocardial infarction, and clinically relevant bleeding. We did a propensity-adjusted multivariable analysis to determine the relation between platelet reactivity and subsequent adverse events. This study is registered with ClinicalTrials.gov , number NCT00638794. Findings Between Jan 7, 2008, and Sept 16, 2010, 8665 patients were prospectively enrolled at 11 sites, of which 8582 were eligible. At 1-year follow-up, stent thrombosis had occurred in 70 (0·8%) patients, myocardial infarction in 269 (3·1%), clinically relevant bleeding in 531 (6·2%), and death in 161 (1·9%) patients. High platelet reactivity on clopidogrel was strongly related to stent thrombosis (adjusted HR 2·49 95% CI 1·43–4·31, p=0·001) and myocardial infarction (adjusted HR 1·42 1·09–1·86, p=0·01), was inversely related to bleeding (adjusted HR 0·73 0·61–0·89, p=0·002), but was not related to mortality (adjusted HR 1·20 0·85–1·70, p=0·30). High platelet reactivity on aspirin was not significantly associated with stent thrombosis (adjusted HR 1·46 0·58–3·64, p=0·42), myocardial infarction, or death, but was inversely related to bleeding (adjusted HR 0·65 0·43–0·99, p=0·04). Interpretation The findings from this study emphasise the counter-balancing effects of haemorrhagic and ischaemic complications after stent implantation, and suggest that safer drugs or tailored strategies for the use of more potent agents must be developed if the benefits of greater platelet inhibition in patients with cardiovascular disease are to be realised. Funding Boston Scientific, Abbott Vascular, Medtronic, Cordis, Biosensors, The Medicines Company, Daiichi-Sankyo, Eli Lilly, Volcano, and Accumetrics
Objectives The aim of this study was to assess the feasibility, safety, and preliminary efficacy of a novel percutaneous left ventricular partitioning device (VPD) in patients with chronic heart ...failure (HF) and a prior anterior myocardial infarction. Background Anterior myocardial infarction is frequently followed by left ventricular remodeling, HF, and increased long-term morbidity and mortality. Methods Thirty-nine patients were enrolled in a multinational, nonrandomized, longitudinal investigation. The primary end point was an assessment of safety, defined as the successful delivery and deployment of the VPD and absence of device-related major adverse cardiac events over 6 months. Secondary (exploratory) efficacy end points included changes in hemodynamics and functional status and were assessed serially throughout the study. Results Ventricular partitioning device placement was not attempted in 5 (13%) of 39 subjects. The device was safely and successfully implanted in 31 (91%) of the remaining 34 patients or 79% of all enrolled patients. The 6-month rate of device-related major adverse cardiac event occurred in 5 (13%) of 39 enrolled subjects and 5 (15%) of 34 treated subjects, with 1 additional event occurring between 6 and 12 months. For patients discharged with the device to 12 months (n = 28), New York Heart Association class (2.5 ± 0.6 to 1.3 ± 0.6, P < .001) and quality-of-life scores (38.6 ± 6.1 to 28.4 ± 4.4, P < .002) improved significantly; however, the 6-minute hall walk distance (358.5 ± 20.4 m to 374.7 ± 25.6 m, P nonsignificant) only trended toward improvement. Conclusions The left VPD appears to be relatively safe and potentially effective in the treatment for patients with HF and a prior anterior myocardial infarction. However, these limited results suggest the need for further evaluation in a larger randomized controlled trial.
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.
Objectives The aim of this study was to define the prevalence and significance of myocardial edema in patients with non–ST-segment elevation acute coronary syndrome (NSTE-ACS). Background Most ...patients with NSTE-ACS undergo angiography, yet not all have obstructive coronary artery disease (CAD) requiring revascularization. Identifying patients with myocardium at risk could enhance the effectiveness of an early invasive strategy. Cardiac magnetic resonance (CMR) can demonstrate edematous myocardium subjected to ischemia but has not been used to evaluate NSTE-ACS patients. Methods One hundred consecutive patients with NSTE-ACS were prospectively enrolled to undergo 30-min CMR, including T2-weighted edema imaging and late gadolinium enhancement before coronary angiography. Clinical management including revascularization decision-making was performed without CMR results. Results Of 88 adequate CMR studies, 57 (64.8%) showed myocardial edema. Obstructive CAD requiring revascularization was present in 87.7% of edema-positive patients versus 25.8% of edema-negative patients (p < 0.001). By multiple logistic regression analysis after adjusting for late gadolinium enhancement, perfusion, and wall motion scores, TIMI risk score was not predictive of obstructive CAD. Conversely, an increase in T2 score by 1 U increased the odds of subsequent coronary revascularization by 5.70 times (95% confidence interval: 2.38 to 13.62, p < 0.001). Adjusting for peak troponin-I, patients with edema showed a higher hazard of a cardiovascular event or death within 6 months after NSTE-ACS compared with those without edema (hazard ratio: 4.47, 95% confidence interval: 1.00 to 20.03; p = 0.050). Conclusions In NSTE-ACS patients, rapid CMR identifies reversibly injured myocardium due to obstructive CAD and predicts worse outcomes. Identifying myocardium at risk may help direct appropriate patients toward early invasive management.
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 )
Anemic patients remain at increased risk of ischemic and bleeding events. Whether or not the effects of hemoglobin levels on thrombotic and bleeding risk are independent of platelet reactivity on ...clopidogrel, however, remains unknown. Patients from the Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents (ADAPT-DES) study were categorized by the presence of anemia at baseline, defined according the World Health Organization criteria. Platelet reactivity was measured with VerifyNow assay; high platelet reactivity (HPR) on clopidogrel was defined as platelet reactive units value >208. Out of 8413 patients included in the study cohort, 1816 (21.6%) had anemia. HPR was more prevalent in patients with anemia (58.3% vs 38.4%; p<0.001), an association that persisted following multivariable adjustment. Patients with anemia had higher 2-year rates of major adverse cardiac events (MACE; 9.5% vs 5.6%; p<0.0001), major bleeding (11.8% vs 7.7%; p<0.0001), and all-cause mortality (4.0% vs 1.4%; p<0.0001); however, following adjustment for baseline clinical confounders, including HPR, anemia was no longer associated with MACE (adjusted hazard ratio HR: 1.22; 95% confidence interval CI: 0.98–1.51; p=0.07), but was still significantly associated with all-cause mortality (adjusted HR: 1.61; 95% CI: 1.23–2.12; p<0.0001) and major bleeding (adjusted HR: 1.42; 95% CI: 1.20–1.68; p<0.0001). In conclusion, anemia independently correlated with HPR. After PCI with drug-eluting stents, anemia at baseline was significantly associated with higher 2-year hemorrhagic and mortality risk; conversely, its association with ischemic risk was attenuated following multivariable adjustment, including HPR.
Abstract Background The incidence, predictors, and prognostic impact of post-discharge bleeding (PDB) after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation are ...unclear. Objectives This study sought to characterize the determinants and consequences of PDB after PCI. Methods The prospective ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) study was used to determine the incidence and predictors of clinically relevant bleeding events occurring within 2 years after hospital discharge. The effect of PDB on subsequent 2-year all-cause mortality was estimated by time-adjusted Cox proportional hazards regression. Results Among 8,582 “all-comers” who underwent successful PCI with DES in the ADAPT-DES study, PDB occurred in 535 of 8,577 hospital survivors (6.2%) at a median time of 300 days (interquartile range: 130 to 509 days) post-discharge. Gastrointestinal bleeding (61.7%) was the most frequent source of PDB. Predictors of PDB included older age, lower baseline hemoglobin, lower platelet reactivity on clopidogrel, and use of chronic oral anticoagulation therapy. PDB was associated with higher crude rates of all-cause mortality (13.0% vs. 3.2%; p < 0.0001). Following multivariable adjustment, PDB was strongly associated with 2-year mortality (hazard ratio HR: 5.03; p < 0.0001), with an effect size greater than that of post-discharge myocardial infarction (PDMI) (HR: 1.92; p = 0.009). Conclusions After successful PCI with DES in an unrestricted patient population, PDB is not uncommon and has a strong relationship with subsequent all-cause mortality, greater that that associated with PDMI. Efforts to reduce PDB may further improve prognosis after successful DES implantation. (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents ADAPT-DES; NCT00638794 )
PDF
