Impact of high on-treatment platelet reactivity on outcomes following PCI in patients on hemodialysis: An ADAPT-DES substudy.

OBJECTIVES: We sought to compare clinical outcomes after percutaneous coronary intervention (PCI) in patients on versus not on hemodialysis (HD) and examine whether high on-treatment platelet reactivity (HPR) further impacts outcomes among patients on HD. BACKGROUND: Both chronic kidney disease (CKD) and HPR are predictors of major adverse cardiac events (MACE) after PCI. METHODS: Two-year outcomes of patients from the prospective, multicenter ADAPT-DES study (N = 8,582) were analyzed according to HD status at enrollment. All patients underwent platelet function testing with the VerifyNow assay; HPR on clopidogrel was defined as P2Y12 reaction units (PRU) >208. RESULTS: Compared with non-HD patients, patients on HD (n = 85) had significantly higher baseline PRU (median 254 vs. 188, p = .001) and more frequently had HPR (61.7% vs. 42.5%, p < .001). HD was associated with increased 2-year rates of MACE (death, myocardial infarction (MI) or definite stent thrombosis (ST); 23.4% vs. 10.7%, p < .001). HD was also strongly associated with 2-year overall mortality, cardiac death, MI, target vessel revascularization, major bleeding, stroke and ST. Following adjustment for HPR and other covariates, HD was independently associated with overall mortality, MI, ST, and major bleeding at 2 years. The relationship between HD status and 2-year MACE was consistent in patients with and without HPR (Pinteraction = .78). CONCLUSIONS: Nearly two-thirds of patients on HD exhibited HPR on clopidogrel, and both HD and HPR were independently associated with 2-year adverse outcomes after DES implantation. However, the deleterious impact of HD on clinical outcomes was present in both patients with and without HPR.

Adverse events in patients with high platelet reactivity following successful chronic total occlusion PCI: The Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents (ADAPT-DES) study.

BACKGROUND: Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) typically requires a greater number of stents and longer stent length than non-CTO PCI, placing these patients at greater risk for adverse ischemic events. We sought to determine whether the association between high platelet reactivity (HPR) and the risk of ischemic events is stronger after CTO than non-CTO PCI. METHODS: Patients undergoing successful PCI in the multicenter ADAPT-DES study were stratified according to whether they underwent PCI of a CTO. HPR was defined as VerifyNow platelet reaction units >208. The study primary endpoint was the 2-year risk target vessel failure ([TVF] defined as cardiac death, myocardial infarction, or target lesion revascularization). RESULTS: CTO PCI was performed in 400 of 8448 patients. HPR was present in 34.5% of CTO PCI patients and 43.1% of non-CTO PCI patients (P = .0007). Patients undergoing CTO PCI with versus without HPR had significantly higher 2-year rates of TVF (15.0% versus 8.3%, P = .04) without significant differences in bleeding. HPR was an independent predictor of 2-year TVF (adjusted HR 1.16, 95% CI 1.02-1.34, P = .03) whereas CTO PCI was not (adjusted HR 0.89, 95% CI 0.65-1.22, P = .48). There was a significant interaction between CTO versus non-CTO PCI and PRU as a continuous variable for 2-year TVF (Pinteraction = 0.02). CONCLUSIONS: In ADAPT-DES, HPR was associated with an increased 2-year risk of TVF after PCI, an association that was at least as strong after CTO PCI compared with non-CTO PCI.

Impact of high on-aspirin platelet reactivity on outcomes following successful percutaneous coronary intervention with drug-eluting stents.

BACKGROUND: Whether high on-aspirin platelet reactivity (HAPR) confers an increased risk of adverse outcomes after percutaneous coronary intervention (PCI) remains unclear. We sought to examine the specific relationship between HAPR and clinical outcomes in ADAPT-DES. METHODS: A total of 8,526 "all-comer" patients in the ADAPT-DES registry who underwent placement of drug-eluting stents (DES) and were treated with aspirin and clopidogrel were assessed to measure platelet reactivity. HAPR was characterized as ≥550 aspirin reaction units and high on-clopidogrel platelet reactivity as >208 P2Y12 reaction units. Univariable and propensity-adjusted multivariable analyses were used to assess the relationship between HAPR and clinical outcomes. RESULTS: HAPR was present in 478 (5.6%) patients. Patients with HAPR were older and had more comorbid illnesses and more complex coronary anatomy. During 2-year follow-up, HAPR was not associated with increased rates of major adverse cardiac events (MACE), stent thrombosis, myocardial infarction, or all-cause mortality. In propensity-adjusted multivariable analyses, HAPR was not an independent predictor of MACE after successful PCI (multivariable adjusted hazard ratio: 1.04; 95% CI 0.64-1.69, P = .87). Nor was HAPR associated with reduced bleeding. Even among patients with concomitant high on-clopidogrel platelet reactivity, HAPR was not associated with worse ischemic outcomes (adjusted hazard ratio for 2-year MACE: 1.06; 95% CI 0.55-2.00, P = .87). CONCLUSIONS: HAPR was infrequently present in a large registry of patients undergoing PCI. There was no clear relationship between HAPR and 2-year clinical outcomes. Investigations of antiplatelet regimens without aspirin after DES implantation are ongoing and should inform future management of patients undergoing PCI.

Prediction of 1-year mortality and impact of bivalirudin therapy according to level of baseline risk: A patient-level pooled analysis from three randomized trials.

OBJECTIVES: We aimed to construct a predictive model for one-year mortality in patients undergoing invasive coronary evaluation and to examine the impact of bivalirudin on survival according to the level of baseline risk. BACKGROUND: Compared to heparin plus GP IIb/IIIa inhibitors (HEP/GPI), bivalirudin decreases bleeding complications in a range of clinical presentations. The impact of preprocedural risk assessment on survival and whether this is modified by bivalirudin, has not been investigated in detail. METHODS: We examined patient-level data from the REPLACE-2, ACUITY, and HORIZONS-AMI trials (n = 18,819) to construct a risk-adjusted mortality model using baseline clinical variables. RESULTS: One-year mortality occurred in 287 patients (3.1%) assigned to bivalirudin and 336 patients (3.6%) assigned to HEP/GPI (HR 0.85; 95% CI, 0.73-1.00; P = 0.048). Using 11 highly significant predictors of mortality, we developed an integer-risk score to classify patients into risk tertiles. High-risk patients had a rate of 1-year mortality over 9-fold greater than low-risk patients. Consequently, the absolute mortality reduction attributed to bivalirudin was more marked in high-risk patients: 3.1% (-0.8% to 7.0%) in the overall cohort, 4.8% (0.5% to 9.2%) in the PCI cohort (P-interaction versus intermediate and low risk categories, 0.09 and P = 0.02, respectively). CONCLUSIONS: In patients undergoing invasive coronary evaluation, 1-year mortality can be predicted using baseline variables. Bivalirudin treatment (versus HEP/GPI) conferred a survival benefit.

Relationship between intravascular ultrasound guidance and clinical outcomes after drug-eluting stents: the assessment of dual antiplatelet therapy with drug-eluting stents (ADAPT-DES) study.

BACKGROUND: Prior small to modest-sized studies suggest a benefit of intravascular ultrasound (IVUS) guidance in noncomplex lesions. Whether IVUS guidance is associated with improved clinical outcomes after drug-eluting stent (DES) implantation in an unrestricted patient population is unknown. METHODS AND RESULTS: Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents (ADAPT-DES) was a prospective, multicenter, nonrandomized "all-comers" study of 8583 consecutive patients at 11 international centers designed to determine the frequency, timing, and correlates of stent thrombosis and adverse clinical events after DES. Propensity-adjusted multivariable analysis was performed to examine the relationship between IVUS guidance and 1-year outcomes. IVUS was utilized in 3349 patients (39%), and larger-diameter devices, longer stents, and/or higher inflation pressures were used in 74% of IVUS-guided cases. IVUS guidance compared with angiography guidance was associated with reduced 1-year rates of definite/probable stent thrombosis (0.6% [18 events] versus 1.0% [53 events]; adjusted hazard radio, 0.40; 95% confidence interval, 0.21-0.73; P=0.003), myocardial infarction (2.5% versus 3.7%; adjusted hazard radio, 0.66; 95% confidence interval, 0.49-0.88; P=0.004), and composite adjudicated major adverse cardiac events (ie, cardiac death, myocardial infarction, or stent thrombosis) (3.1% versus 4.7%; adjusted hazard radio, 0.70; 95% confidence interval, 0.55-0.88; P=0.002). The benefits of IVUS were especially evident in patients with acute coronary syndromes and complex lesions, although significant reductions in major adverse cardiac events were present in all patient subgroups those with including stable angina and single-vessel disease. CONCLUSIONS: In ADAPT-DES, the largest study of IVUS use to date, IVUS guidance was associated with a reduction in stent thrombosis, myocardial infarction, and major adverse cardiac events within 1 year after DES implantation. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00638794.

Predictors and impact of target vessel revascularization after stent implantation for acute ST-segment elevation myocardial infarction: lessons from HORIZONS-AMI.

BACKGROUND: Target vessel revascularization (TVR) may compromise the benefits of primary percutaneous coronary intervention in ST-segment elevation myocardial infarction (STEMI) We set out to identify the predictors and examine the impact of TVR after STEMI in patients receiving a coronary stent. METHODS: In HORIZONS-AMI, 3,602 patients with STEMI were randomized to bivalirudin versus heparin and a glycoprotein IIb/IIIa inhibitor. Stents were implanted in 3,202 patients (2,982 were randomized to bare-metal stents versus paclitaxel-eluting stents, and 220 received nonrandomized stents). RESULTS: Target vessel revascularization occurred in 219 patients (6.9%) at 1 year and in 437 patients (14.4%) at 3 years. Target vessel revascularization was ischemia-driven in 418 cases (95.7%). Target vessel revascularization was due to restenosis in 219 patients (50.1%), definite stent thrombosis in 124 (28.4%), and disease progression in 94 (21.5%). Independent predictors of TVR were more extensive coronary artery disease, smaller vessel size, longer lesion length and the number of stents implanted, post-percutaneous coronary intervention diameter stenosis, symptom onset to balloon time, treatment with bare-metal stents rather than paclitaxel-eluting stents, and scheduled angiographic follow-up. Target vessel revascularization was an independent predictor of subsequent myocardial infarction (hazard ratio [HR] 5.25, P < .0001), ST (HR 5.98, P < .0001), and major bleeding (HR 5.25, P < .0001) but not mortality (HR 0.88, P = .61). CONCLUSIONS: In HORIZONS-AMI, TVR within 3 years after stent implantation was performed in ~1 of every 7 patients and was associated with more extensive coronary disease, more complex procedures, and bare metal stents. Target vessel revascularization was often due to stent thrombosis and disease progression as well as restenosis and was strongly associated with adverse outcomes but not mortality.

Sex-based differences in bleeding and long term adverse events after percutaneous coronary intervention for acute myocardial infarction: three year results from the HORIZONS-AMI trial.

BACKGROUND: Studies have shown sex-based disparities in ST-segment elevation myocardial infarction (STEMI) management and prognosis. We sought to compare women and men undergoing primary percutaneous coronary intervention (PCI) for STEMI in a large, prospective, contemporary context. METHODS: The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial randomized 3,602 patients (23.4% women and 76.6% men) with STEMI presenting within 12 hr of onset of symptoms to bivalirudin or heparin plus glycoprotein IIb/IIIa inhibitors and to PCI with drug-eluting or bare metal stents. RESULTS: Compared with men, women presented later after symptom onset and were more often treated with medical management alone (6.9% vs. 4.7%; P = 0.01). Women had significantly higher rates of 3-year major adverse cardiac events (MACE) and major bleeding. After adjusting for baseline differences, female sex remained an independent predictor of major bleeding (hazard ratio [HR] 1.81, 95% confidence interval [CI] 1.41-2.33; P < 0.0001) but not of MACE (HR 1.09; 95% CI 0.91-1.32; P = 0.35). CONCLUSIONS: This study found that women with STEMI are at increased risk of bleeding as compared to men. While female sex may not directly contribute to increased risk of MACE, it is, however, associated with the presence of comorbidities that increase the risk of ischemic events long-term. Further dedicated studies are needed to confirm these findings and to assess strategies to optimize both the initial emergent treatment and long-term management in this high-risk subset. © 2014 Wiley Periodicals, Inc.

Contrast-induced acute kidney injury after primary percutaneous coronary intervention: results from the HORIZONS-AMI substudy.

AIM: We sought to examine the short- and long-term outcomes of patients who developed contrast-induced acute kidney injury (CI-AKI; defined as an increase in serum creatinine of ≥0.5 mg/dL or a 25% relative rise within 48 h after contrast exposure) from the large-scale HORIZONS-AMI trial. METHODS AND RESULTS: Multivariable analyses were used to identify predictors of CI-AKI, as well predictors of the primary and secondary endpoints. The incidence of CI-AKI in this cohort of ST-segment elevation myocardial infarction (STEMI) patients was 16.1% (479/2968). Predictors of CI-AKI were contrast volume, white blood cell count, left anterior descending infarct-related artery, age, anaemia, creatinine clearance <60 mL/min, and history of congestive heart failure. Patients with CI-AKI had higher rates of net adverse clinical events [NACE; a combination of major bleeding or composite major adverse cardiac events (MACE; consisting of death, reinfarction, target vessel revascularization for ischaemia, or stroke)] at 30 days (22.0 vs. 9.3%; P < 0.0001) and 3 years (40.3 vs. 24.6%; P < 0.0001). They also had higher rates of mortality at 30 days (8.0 vs. 0.9%; P < 0.0001) and 3 years (16.2 vs. 4.5%; P < 0.0001). Multivariable analysis confirmed CI-AKI as an independent predictor of NACE [hazard ratio ([HR), 1.53; 95% confidence interval (CI), 1.23-1.90; P = 0.0001], MACE (HR, 1.56; 95% CI, 1.23-1.98; P = 0.0002), non-coronary artery bypass grafting major bleeding (HR, 2.07; 95% CI, 1.57-2.73; P < 0.0001), and mortality (HR, 1.80; 95% CI, 1.19-2.73; P = 0.005) at 3-year follow-up. CONCLUSION: Contrast-induced acute kidney injury is associated with poor short- and long-term outcomes after primary percutaneous coronary intervention in STEMI.

Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study.

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 8583 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.

New generation drug-eluting stents for ST-elevation myocardial infarction: a new paradigm for safety.

OBJECTIVES: The objective of this study is to compare the long-term safety of new generation drug-eluting stents (DES) with early generation DES and bare metal stents (BMS) for ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Early generation DES for STEMI have reduced target vessel revascularization, but have more very late ST compared with BMS raising concerns about their safety. New compared with early generation DES have lower rates of ST, but there are limited data in STEMI patients. METHODS: From 2003 to 2011, 3,464 STEMI patients were treated with BMS (n = 1,187), early generation DES (n = 1,525), or new generation DES (n = 752) and were followed for 1-9 years. RESULTS: Patients with new generation DES were younger, had less cardiogenic shock, and less prior infarction versus BMS, and more hypertension versus early generation DES. At 2 years, new generation DES had lower mortality (4.0% vs. 12.4%, P < 0.001), similar reinfarction (4.4% vs. 5.1%, P = 0.35), and less ST (1.4% vs. 3.8%, P = 0.031) versus BMS; and similar mortality (4.0% vs. 5.8%, P = 0.23), similar reinfarction (4.4% vs. 5.2%, P = 0.64), and trends for less ST (1.4% vs. 3.3%, P = 0.17) versus early generation DES. By Cox multivariable analyses, BMS had more ST than new generation DES (HR [95% CI] = 1.93 [1.01-3.66], P = 0.045). CONCLUSIONS: New generation DES in STEMI patients have less ST compared to BMS and trends for less ST compared to early generation DES. These data suggest a new safety paradigm and should encourage the use of new generation DES in most STEMI patients treated with primary percutaneous coronary intervention (PCI).

Very late hazard with stenting versus balloon angioplasty for ST-elevation myocardial infarction: a 16-year single-center experience.

OBJECTIVES: This study compares very late outcomes following primary percutaneous coronary intervention for ST-elevation myocardial infarction (STEMI) with stenting versus balloon angioplasty (BA). BACKGROUND: Stenting compared with BA for STEMI improves outcomes at 6-12 months, but comparisons beyond 6-12 months have not been studied. Recent studies have shown that stent thrombosis (ST) continues to increase beyond 3-5 years and may be higher with drug-eluting stents (DES) than bare metal stents (BMS). We hypothesized that there may be a very late hazard with stenting versus BA due to very late ST. METHODS: From 1994 to 2010 consecutive patients with STEMI treated with BA (n = 601) or stenting (n = 1,594) were prospectively enrolled in our registry and followed for 1-16 years. RESULTS: Patients treated with BA were older, were more often female, had more three-vessel disease, and had smaller vessels. Stented patients had trends for less stent/lesion thrombosis (ST/LT) and target vessel (TV) reinfarction at 1 year. In landmark analyses >1 year, stented patients had more very late ST/LT (6.1% vs. 2.9%, P = 0.002) and more TV reinfarction (7.9% vs. 3.1%, P < 0.001) which remained significant after adjusting for baseline risk. The greatest differences in very late outcomes were between DES and BA, but there were also significant differences between BMS and BA. CONCLUSIONS: There appears to be a very late hazard with stenting versus BA for STEMI. These data should encourage new strategies for prevention of very late ST with both BMS and DES including the development of bio-absorbable polymers and stent platforms.

D-dimer levels predict ischemic and hemorrhagic outcomes after acute myocardial infarction: a HORIZONS-AMI biomarker substudy.

D-dimer is a product of cross linked fibrin degradation and is a measure of the amount of fibrin turnover. As such, D-dimer might be of utility in the prediction of both thrombotic and hemorrhagic events. Therefore, the aim of the present study was to evaluate whether elevated D-dimer levels on admission and at discharge could predict subsequent ischemic and hemorrhagic events in patients with acute myocardial infarction (AMI). D-dimer was measured on admission and at discharge in 461 out of a total of 3,602 patients in the HORIZONS-AMI trial, as part of the formal prespecified biomarker substudy. The predictive value for major adverse cardiovascular events (MACE) and non-CABG major bleeding after 3 year follow up was investigated by stratifying patients in groups of D-dimer level and comparing event rates using Kaplan-Meier and calculating hazard ratios using Cox proportional hazards models. D-dimer levels ≥ 0.71 µg/mL on admission were associated with an adjusted hazard ratio of 2.58 for MACE (p = 0.0014) and 4.61 for major bleeding (p = 0.0018). A discharge D-dimer level ≥ 1.26 µg/mL was associated with a higher risk for MACE by univariate analysis (HR 1.88, p = 0.037), but lost its significance after multivariate adjustment (HR 1.77, p = 0.070). High D-dimer levels on admission were associated with a higher risk of MACE and non-CABG major bleeding in STEMI patients undergoing pPCI.

Are adverse events following an invasive strategy in patients with non-ST-segment elevation acute coronary syndromes more frequent at US sites versus non-US sites? Analysis from the ACUITY trial.

OBJECTIVE: To compare outcomes between US and non-US (OUS) sites in patients with non ST-elevation acute coronary syndromes (NSTEACS) and to evaluate potential reasons for differences in outcomes. BACKGROUND: There are little data comparing outcomes at US versus OUS sites in patients with NSTEACS managed with an invasive strategy. METHODS: The ACUITY trial randomized 13,819 patients with NSTEACS in 17 countries to an invasive approach with one of three strategies: (1) heparin plus glycoprotein platelet inhibitors (GPI), (2) bivalirudin plus GPI, or (3) bivalirudin alone. RESULTS: US patients were more often female, were younger, heavier, and had more diabetes, prior myocardial infarction (MI), and prior bypass surgery. US patients were less often treated with percutaneous coronary intervention but had more frequent drug-eluting stent use. US patients had lower mortality and higher MI rates at 30 days and 1 year and higher composite ischemic outcome at 30 days. After adjusting for differences in baseline variables, US patients had higher rates of MI and composite ischemic outcome at 30 days and higher rates of MI at 1 year {HR [95% confidence interval (CI)] = 1.36 [1.18-1.56], P < 0.0001} with no differences in mortality. There were no differences in treatment effects comparing bivalirudin with the other strategies between US and OUS sites. CONCLUSIONS: US versus OUS patients with NSTEACS had higher adjusted rates of MI and ischemia. The reasons for these differences are not clear but may be due to unmeasured confounders, different thresholds for event reporting, or valid differences in systems of care which may impact outcomes.

Impact of advanced age on the safety and effectiveness of paclitaxel-eluting stent implantation in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: The HORIZONS-AMI trial.

OBJECTIVES: To assess the impact of age on safety and efficacy of paclitaxel-eluting stent (PES) implantation during primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: The benefits of paclitaxel-eluting stent (PES) implantation during primary PCI were confirmed by the long-term results of the HORIZONS-AMI trial. Whether the effects of PES are independent of age has not been reported. METHODS: Data on 3,006 patients from the HORIZONS-AMI study randomized in a 3:1 ratio to PES or bare-metal stent (BMS) in whom at least one stent was implanted were assessed. There were 2,302 (76.6%) patients <70, and 704 patients ≥70 years of age. RESULTS: At 3 years, among older patients a trend toward lower risk of major adverse cardiac events (MACE; death from any cause, stroke, reinfarction and unplanned revascularization for ischemia) related to PES use was observed (PES vs. BMS: 18.0% vs. 21.3%; P = 0.07). There was also a trend for reduction of MACE related to PES in older patients (26.4% vs. 33.1%; P = 0.09). Both, patients <70 and ≥70 years of age treated with PES were at lower risk for ischemic target vessel revascularization. However, a higher risk of major bleeding in elderly patients treated with PES was observed (P = 0.02 for interaction between age group and PES effects). No interaction between age and stent type in terms of the risk of other clinical end points, including all-cause death, was confirmed. CONCLUSIONS: For STEMI patients undergoing primary PCI, the implantation of PES as compared with BMS reduced ischemic TVR, and this effect was independent of age.

Coronary reperfusion and clinical outcomes after thrombus aspiration during primary percutaneous coronary intervention: findings from the HORIZONS-AMI trial.

OBJECTIVES: To assess the quality of coronary reperfusion and long-term clinical outcomes of patients enrolled in the HORIZONS-AMI trial according to the use of thrombus aspiration (TA). BACKGROUND: The impact of manual TA on microvascular perfusion and clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI) is unsettled. METHODS: In this retrospective, nonrandomized, subgroup analysis, the authors evaluated thrombolysis in myocardial infarction (TIMI) flow, tissue myocardial perfusion grade (TMPG), ST-segment resolution (STR), net adverse clinical events (NACE), and major adverse cardiac events (MACE) in patients undergoing pPCI with or without manual TA. RESULTS: A total of 318 patients had pPCI with upfront TA, and 2,917 patients had pPCI without TA. Patients who had TA were more likely to have TIMI 0/1 flow at baseline (75.1% vs. 63.7%, P < 0.0001). There was no difference in the rates of final TIMI 3 flow (90.2% vs. 92.3%, P = 0.19) or dynamic TMPG 2-3 (77.4% vs. 76.4%, P = 0.68). STR ≥70% was similar in both groups at 60 minutes but higher in the TA group at discharge (71.8% vs. 64.6%, P = 0.02). After multivariable adjustment, TA did not predict MACE at 30 days (HR 0.96 [0.51-1.80], P = 0.90), 1 year (HR 1.03 [0.68-1.55], P = 0.89), or 3 years (HR 1.13 [0.86-1.48], P = 0.39). Stent thrombosis did not differ at 1 year or 3 years. CONCLUSIONS: In STEMI patients undergoing pPCI, the use of manual TA was associated with improved STR at discharge, but not with any difference in final TIMI flow, TMPG, or MACE.

Relationship between biomarkers and subsequent bleeding risk in ST-segment elevation myocardial infarction patients treated with paclitaxel-eluting stents: a HORIZONS-AMI substudy.

Major bleeding complications in STEMI patients result in significant mortality, morbidity and healthcare cost. Identification of patients at increased risk of bleeding is therefore essential. New biomarkers might be of incremental value to identify patients at risk for bleeding after primary PCI. A total of 26 biomarkers were measured at enrolment and analyzed at a central core laboratory in 464 STEMI patients in the HORIZONS-AMI trial. We investigated the relationship between tertiles of biomarker and in hospital non-CABG major bleeding. In hospital non-CABG major bleeding occurred in 3.7% of patients (n = 17). Increasing levels of cystatin C and D-dimer at admission were associated with higher rates of in hospital major bleeding. After adjustment for a risk score for bleeding, the odds ratio for in hospital major bleeding was 3.13 for cystatin C > 2.04 mg/L (p = 0.046) and 3.28 for ESAM > 34 ng/mL (p = 0.037). In this exploratory analysis of the HORIZONS-AMI biomarker substudy, high cystatin C and ESAM levels were associated with a higher risk of major bleeding. Larger studies are warranted to confirm the prognostic value of cystatin C and ESAM for major bleeding in STEMI patients.

On-Treatment Platelet Reactivity and Ischemic Outcomes in Patients With Diabetes Mellitus: Two-Year Results From ADAPT-DES.

Background Diabetes mellitus and high platelet reactivity (HPR) on clopidogrel are both associated with increased risk of ischemic events after percutaneous coronary intervention, but whether the HPR-associated risk of adverse ischemic events differs by diabetes mellitus status is unknown. Methods and Results ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) was a prospective, multicenter registry of patients treated with coronary drug-eluting stents. HPR was defined as P2Y12 reaction units >208 by the VerifyNow point-of-care assay. Cox multivariable analysis was used to assess whether HPR-associated risk of major adverse cardiac events (MACE; cardiac death, myocardial infarction, or stent thrombosis) varied for patients with insulin-treated diabetes mellitus (ITDM), non-ITDM, and no diabetes mellitus. Diabetes mellitus and HPR were included in an interaction analysis. Of 8582 patients enrolled, 2429 (28.3%) had diabetes mellitus, of whom 998 (41.1%) had ITDM. Mean P2Y12 reaction units were higher in patients with diabetes mellitus versus without diabetes mellitus, and HPR was more frequent in patients with diabetes mellitus. HPR was associated with consistently increased 2-year rates of MACE in patients with and without diabetes mellitus (Pinteraction=0.36). A significant interaction was present between HPR and non-insulin-treated diabetes mellitus versus ITDM for 2-year MACE (adjusted hazard ratio [HR] for non-ITDM, 2.28 [95% CI, 1.39-3.73] versus adjusted HR for ITDM, 1.02 [95% CI, 0.70-1.50]; Pinteraction=0.01). Conclusions HPR was more common in patients with diabetes mellitus and was associated with an increased risk of MACE in both patients with and without diabetes mellitus. In patients with diabetes mellitus, a more pronounced effect of HPR on MACE was present in lower-risk non-ITDM patients than in higher-risk patients with ITDM. Registration URL: https://clinicaltrials.gov/ct2/show/NCT00638794; Unique identifier: NCT00638794. ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents).

Frequency and predictors of stent thrombosis after percutaneous coronary intervention in acute myocardial infarction.

BACKGROUND: Concerns persist regarding the risk of stent thrombosis in the setting of primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. METHODS AND RESULTS: The Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial included 3602 patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention who were randomized to heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) (n=1802) versus bivalirudin monotherapy (n=1800). Stents were implanted in 3202 patients, including 2261 who received drug-eluting stents and 861 who received only bare metal stents. Definite or probable stent thrombosis within 2 years occurred in 137 patients (4.4%), including 28 acute events (0.9%), 49 subacute events (1.6%), 32 late events (1.0%), and 33 very late events (1.1%). The 2-year cumulative rates of stent thrombosis were 4.4% with both drug-eluting stents and bare metal stents (P=0.98) and 4.3% versus 4.6% in patients randomized to bivalirudin monotherapy versus heparin plus a GPI, respectively (P=0.73). Acute stent thrombosis occurred more frequently in patients assigned to bivalirudin compared with heparin plus a GPI (1.4% versus 0.3%; P<0.001), whereas stent thrombosis after 24 hours occurred less frequently in patients with bivalirudin compared with heparin plus a GPI (2.8% versus 4.4%; P=0.02). Pre-randomization heparin and a 600-mg clopidogrel loading dose were independent predictors of reduced acute and subacute stent thrombosis, respectively. CONCLUSIONS: Stent thrombosis is not uncommon within the first 2 years after primary percutaneous coronary intervention in ST-segment elevation myocardial infarction, and occurs with similar frequency in patients receiving drug-eluting stents versus bare metal stents and bivalirudin alone versus heparin plus a GPI. Optimizing adjunct pharmacology including early antithrombin therapy preloading with a potent antiplatelet therapy may further reduce stent thrombosis in ST-segment elevation myocardial infarction.

Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial.

BACKGROUND: Primary results of the HORIZONS-AMI trial have been previously reported. In this final report, we aimed to assess 3-year outcomes. METHODS: HORIZONS-AMI was a prospective, open-label, randomised trial undertaken at 123 institutions in 11 countries. Patients aged 18 years or older were eligible for enrolment if they had ST-segment elevation myocardial infarction (STEMI), presented within 12 h after onset of symptoms, and were undergoing primary percutaneous coronary intervention. By use of a computerised interactive voice response system, we randomly allocated patients 1:1 to receive bivalirudin or heparin plus a glycoprotein IIb/IIIa inhibitor (GPI; pharmacological randomisation; stratified by previous and expected drug use and study site) and, if eligible, randomly allocated 3:1 to receive a paclitaxel-eluting stent or a bare metal stent (stent randomisation; stratified by pharmacological group assignment, diabetes mellitus status, lesion length, and study site). We produced Kaplan-Meier estimates of major adverse cardiovascular events at 3 years by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00433966. FINDINGS: Compared with 1802 patients allocated to receive heparin plus a GPI, 1800 patients allocated to bivalirudin monotherapy had lower rates of all-cause mortality (5·9%vs 7·7%, difference -1·9% [-3·5 to -0·2], HR 0·75 [0·58-0·97]; p=0·03), cardiac mortality (2·9%vs 5·1%, -2·2% [-3·5 to -0·9], 0·56 [0·40-0·80]; p=0·001), reinfarction (6·2%vs 8·2%, -1·9% [-3·7 to -0·2], 0·76 [0·59-0·99]; p=0·04), and major bleeding not related to bypass graft surgery (6·9%vs 10·5%, -3·6% [-5·5 to -1·7], 0·64 [0·51-0·80]; p=0·0001) at 3 years, with no significant differences in ischaemia-driven target vessel revascularisation, stent thrombosis, or composite adverse events. Compared with 749 patients who received a bare-metal stent, 2257 patients who received a paclitaxel-eluting stent had lower rates of ischaemia-driven target lesion revascularisation (9·4%vs 15·1%, -5·7% [-8·6 to -2·7], 0·60 [0·48-0·76]; p<0·0001) after 3 years, with no significant differences in the rates of death, reinfarction, stroke or stent thrombosis. Stent thrombosis was high (≥4·5%) in both groups. INTERPRETATION: The effectiveness and safety of bivalirudin monotherapy and paclitaxel-eluting stenting are sustained at 3 years for patients with STEMI undergoing primary percutaneous coronary intervention. FUNDING: Boston Scientific and The Medicines Company.

Paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction.

BACKGROUND: There is no consensus regarding the safety and efficacy of drug-eluting stents, as compared with bare-metal stents, in patients with ST-segment elevation myocardial infarction who are undergoing primary percutaneous coronary intervention (PCI). METHODS: We randomly assigned, in a 3:1 ratio, 3006 patients presenting with ST-segment elevation myocardial infarction to receive paclitaxel-eluting stents (2257 patients) or otherwise identical bare-metal stents (749 patients). The two primary end points of the study were the 12-month rates of target-lesion revascularization for ischemia (analysis powered for superiority) and a composite safety outcome measure of death, reinfarction, stroke, or stent thrombosis (powered for noninferiority with a 3.0% margin). The major secondary end point was angiographic evidence of restenosis at 13 months. RESULTS: Patients who received paclitaxel-eluting stents, as compared with those who received bare-metal stents, had significantly lower 12-month rates of ischemia-driven target-lesion revascularization (4.5% vs. 7.5%; hazard ratio, 0.59; 95% confidence interval [CI], 0.43 to 0.83; P=0.002) and target-vessel revascularization (5.8% vs. 8.7%; hazard ratio, 0.65; 95% CI, 0.48 to 0.89; P=0.006), with noninferior rates of the composite safety end point (8.1% vs. 8.0%; hazard ratio, 1.02; 95% CI, 0.76 to 1.36; absolute difference, 0.1 percentage point; 95% CI, -2.1 to 2.4; P=0.01 for noninferiority; P=0.92 for superiority). Patients treated with paclitaxel-eluting stents and those treated with bare-metal stents had similar 12-month rates of death (3.5% and 3.5%, respectively; P=0.98) and stent thrombosis (3.2% and 3.4%, respectively; P=0.77). The 13-month rate of binary restenosis was significantly lower with paclitaxel-eluting stents than with bare-metal stents (10.0% vs. 22.9%; hazard ratio, 0.44; 95% CI, 0.33 to 0.57; P<0.001). CONCLUSIONS: In patients with ST-segment elevation myocardial infarction who were undergoing primary PCI, implantation of paclitaxel-eluting stents, as compared with bare-metal stents, significantly reduced angiographic evidence of restenosis and recurrent ischemia necessitating repeat revascularization procedures. No safety concerns were apparent at 1 year. (ClinicalTrials.gov number, NCT00433966.)