Urgent Intervention Triage Strategy Trial Research Articles

Safety and efficacy of bivalirudin monotherapy in patients with non-ST-segment elevation acute coronary syndromes with positive biomarkers undergoing percutaneous coronary intervention: a report from the Acute Catheterization and Urgent Intervention Triage Strategy trial

There are limited data on bivalirudin monotherapy in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) with positive biomarkers of myocardial necrosis (troponin and/or creatine kinase-myocardial band isoenzyme). We sought to evaluate the safety and efficacy of bivalirudin monotherapy in patients with positive biomarkers from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. We compared the net adverse clinical events [composite ischemia - (death, myocardial infarction, or unplanned ischemic revascularization) - or noncoronary artery bypass graft surgery (CABG)-related major bleeding] among patients with biomarker-positive NSTE-ACS in the ACUITY trial overall and by antithrombotic strategy. Among 13 819 patients with NSTE-ACS enrolled in ACUITY, 4728 patients presented with positive biomarkers and underwent an early invasive strategy. Of those, 1547 were randomized to heparin plus a glycoprotein IIb/IIIa inhibitor (GPI), 1555 to bivalirudin plus GPI, and 1626 to bivalirudin monotherapy. Compared with biomarker-negative patients, biomarker-positive patients had higher 30-day rates of net adverse clinical events (14.0 vs. 12.4%; P = 0.04), all-cause death (1.3 vs. 0.5%; P = 0.001), cardiac death (1.1 vs. 0.5%; P = 0.005), and non-CABG-related major bleeding (6.5 vs. 5.2%, P = 0.03). At 30 days, bivalirudin monotherapy was associated with significantly less non-CABG-related major bleeding (bivalirudin monotherapy 4.1% vs. bivalirudin plus GPI 8.4% vs. heparin plus GPI 7.1%) with comparable rates of composite ischemia (bivalirudin monotherapy 9.2% vs. bivalirudin plus GPI 9.9% vs. heparin plus GPI 8.4%). In a multivariable model, bivalirudin monotherapy was associated with a significant reduction in non-CABG-related major bleeding but was not associated with an increased risk of death, myocardial infarction, unplanned revascularization or stent thrombosis. Compared with heparin plus GPI or bivalirudin plus GPI, bivalirudin monotherapy provides similar protection from ischemic events with less major bleeding at 30 days among patients with NSTE-ACS and positive biomarkers.

Incidence and Impact of Totally Occluded Culprit Coronary Arteries in Patients Presenting With Non–ST-Segment Elevation Myocardial Infarction

The accuracy of the 12-lead electrocardiogram in detecting coronary artery occlusion is limited. We sought to determine the incidence, distribution, and outcomes of patients who have total occlusion of the culprit artery but present with non-ST-segment elevation myocardial infarction (NSTEMI). The randomized Acute Catheterization and Urgent Intervention Triage Strategy trial enrolled 13,819 patients presenting with non-ST-segment elevation acute coronary syndromes who underwent an early invasive strategy. The present study includes 1,319 patients with baseline biomarker elevation (NSTEMI) and no history of coronary artery bypass graft who underwent percutaneous coronary intervention of a single culprit vessel. We compared the baseline characteristics and outcomes according to whether the culprit vessel was occluded (baseline Thrombolysis In Myocardial Infarction [TIMI] 0 to 1) or patent (TIMI 2 to 3 flow) by angiographic core laboratory assessment. TIMI 0 to 1 flow in the culprit artery was present in 262 of 1,319 (19.9%) patients. The incidence of coronary occlusion was 28.4%, 19.3%, and 12.6% in patients with NSTEMI because of right coronary, left circumflex, and left anterior descending artery disease, respectively. Patients with an occluded culprit artery were more commonly men and had ST-segment deviation ≥1mm. One-year outcomes, including death (3.5% vs 3.0%, p= 0.68) and myocardial infarction (8.4% vs 9.6%, p= 0.47), did not differ significantly between patients with versus without occluded culprit arteries, respectively. In conclusion, the present study demonstrates that the culprit artery is totally occluded in approximately 1 in 5 patients presenting with NSTEMI and single-vessel disease; however, the presence of total occlusion in NSTEMI was not associated with an incremental hazard of death or reinfarction at 1year.

Effect of Anemia on Frequency of Short- and Long-Term Clinical Events in Acute Coronary Syndromes (from the Acute Catheterization and Urgent Intervention Triage Strategy Trial)

There are limited data on the impact of anemia on clinical outcomes in unstable angina and non-ST-segment elevation myocardial infarction treated with an early invasive strategy. We sought to determine the short- and long-term clinical events among patients with and without anemia enrolled in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. Anemia was defined as baseline hemoglobin of <13g/dl for men and <12g/dl for women. The primary end points were composite ischemia (death, myocardial infarction, or unplanned revascularization for ischemia) and major bleeding assessed in-hospital, at 1 month, and at 1 year. Among the 13,819 patients in the ACUITY trial, information regarding anemia was available in 13,032 (94.3%), 2,199 of whom (16.9%) had anemia. Patients with anemia compared with those without anemia had significantly increased adverse event rates in-hospital (composite ischemia 6.6% vs 4.8%, p= 0.0004; major bleeding 7.3% vs 3.3%, p<0.0001), at 1 month (composite ischemia 10% vs 7.2%, p <0.0001, major bleeding 8.8% vs 3.9%, p <0.0001), and 1 year (composite ischemia 21.7% vs 15.3%, p <0.0001). Anemia was an independent predictor of death at 1 year (hazard ratio 1.77, 95% confidence interval [CI] 1.29 to 2.44, p= 0.0005). Composite ischemia was significantly more common among patients who developed in-hospital non-coronary artery bypass surgery major bleeding compared with those who did not (anemic patients 1-year relative risk 2.19, 95% CI 1.67 to 2.88, p <0.0001; nonanemic patients relative risk 2.16, 95% CI 1.76 to 2.65, p <0.0001). In conclusion, in the ACUITY trial, baseline anemia was strongly associated with adverse earlyand late clinical events, especially in those who developed major bleeding.

Usefulness of the SYNTAX Score to Predict Acute Kidney Injury After Percutaneous Coronary Intervention (from the Acute Catheterization and Urgent Intervention Triage Strategy Trial)

The synergy between percutaneous coronary intervention (PCI) with Taxus and cardiac surgery (SYNTAX) score (SS) has prognostic utility for ischemic outcomes in patients undergoing PCI. Acute kidney injury (AKI) after PCI has been demonstrated to be associated with adverse outcomes. However, the relation between the SS and AKI after PCI has yet to be fully investigated. We therefore sought to study this relation in the formal angiographic substudy of the large Acute Catheterization and Urgent Intervention Triage Strategy trial. We stratified 2,268 patients who underwent PCI for non-ST-segment elevation acute coronary syndromes by postprocedural AKI status and by SS tertiles (SS<7, 7 to 12, and >12). We also assessed rates of in-hospital, 30-day, and 1-year adverse outcomes. A total of 226 patients (10%) developed AKI, and rates in the highest Acute Catheterization and Urgent Intervention Triage Strategy SS tertile (>12) were significantly greater than those in the intermediate (7 to 12) and lowest tertiles (<7; 13% vs 8.9% vs 7.7%, respectively, p=0.002). By multivariable analysis, the SS was independently associated with AKI (odds ratio per 10 SS points 1.22, 95% confidence interval 1.04 to 1.43, p=0.02. Rates of major adverse cardiovascular events and net adverse clinical events increased significantly by SS tertile and were more common in patients who developed AKI. Patients who developed AKI experienced higher in-hospital, 30-day, and 1-year rates of mortality. In this large study, the SS was independently associated with AKI after PCI for non-ST-segment elevation acute coronary syndromes, and patients who developed AKI experienced worse short-term and long-term outcomes.

Impact of the Severity of Coronary Artery Calcification on Clinical Events in Patients Undergoing Coronary Artery Bypass Grafting (from the Acute Catheterization and Urgent Intervention Triage Strategy Trial)

The treatment of calcified coronary lesions by percutaneous coronary intervention has been shown to be associated with poor outcomes and an increased rate of complications. However, the impact of coronary calcification in patients undergoing coronary artery bypass grafting (CABG) is unknown. A total of 755 patients presenting with acute coronary syndrome in the Acute Catheterization and Urgent Intervention Triage Strategy trial underwent CABG. Patients were divided into 3 groups according to the presence and extent of coronary calcifications (lesion level: severe, moderate, none to mild) as assessed by an independent angiographic core laboratory. Major ischemic and bleeding outcomes were assessed at 30days and 1year. Severe calcification was found in 103 patients (13.6%), moderate calcification in 249 patients (33.0%), and none-to-mild calcification in 403 patients (53.4%). The presence of severe calcification compared with moderate or none to mild was associated with a significantly higher unadjusted rate of death (11.8% vs 3.7% vs 4.5%, p= 0.006), death or myocardial infarction (MI; 31.1% vs 19.7% vs 16.4%, p= 0.006), and major adverse cardiac event (MACE; 32.0% vs 22.6% vs 20.8%, p= 0.059) at 1year. By multivariate analysis, severe calcification (vs nonsevere calcification) was identified as an independent predictor of 1-year MACE (hazard ratio 1.49, 95% confidence interval 1.01 to 2.21, p= 0.04) and death or MI (hazard ratio 1.77, 95% confidence interval 1.18 to 2.66, p= 0.006). In conclusion, the presence of severe coronary calcification was associated with worse outcomes after CABG, including an increased risk of death. The presence of severe coronary calcification was identified as an independent predictor of MACE and death or MI 1year after CABG.

Nonalcoholic Fatty Liver Disease and Severity of Cardiovascular Disease Manifestations

Nonalcoholic fatty liver disease (NAFLD), characterized by the accumulation of fat in the liver cells in the absence of excessive alcohol intake and other liver disease, affects approximately 15% to 30% of the general population in various countries; its prevalence increases up to 70% to 90% in people with obesity, metabolic syndrome (MetS), or type 2 diabetes mellitus (T2DM). The histological manifestations of NAFLD range from simple steatosis, steatohepatitis (nonalcoholic steatohepatitis [NASH]), liver fibrosis, cirrhosis, and, rarely, hepatocellular carcinoma. The NAFLD is considered to be the hepatic manifestation of the MetS. The NAFLD is strongly associated with increased risk of cardiovascular disease (CVD), and NAFLD is not only a marker but also an early mediator of atherosclerosis. The risk of clinical manifestations of CVD is significantly higher in individuals with NASH than in those with simple steatosis, and the histological severity of NAFLD (ie, steatosis, necroinflammation, and fibrosis) predicts CVD independent of classical risk factors, insulin resistance, and components of the MetS. This suggests that NAFLD might itself confer a degree of CVD risk above and beyond that associated with the individual components of MetS. Key issues remaining to be investigated are the association of NAFLD presence and/or grade (stage) with the severity, and therefore, the prognosis of CVD manifestations (coronary artery disease [CAD], stroke, and peripheral arterial disease [PAD]) and our ability to tackle the negative effect of NAFLD on CVD morbidity and mortality. The results of the study by Agac et al, published in this issue of Angiology, suggest that the prevalence of NAFLD was very high (81.2%) among subjects with acute coronary syndromes (ACS) and that the SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score (SS) may represent a prognostic marker in patients with both non-ST and ST segment elevation ACS. The SS is an angiographic variable that predicts 1-year mortality rates, cardiac death, myocardial infarction, and target vessel revascularization in patients undergoing percutaneous coronary intervention (PCI) and its value is significantly higher in patients with NAFLD than in those without NAFLD (18 + 8 vs 11+ 5, P 1⁄4 .001). Furthermore, in multivariate analysis, increased age (odds ratio [OR] 1.05; 95% confidence interval [CI] 1.00-1.10) and the presence of NAFLD (OR, 13.20; 95% CI, 2.52-69.15) were independent factors associated with the SS value. This suggests that the presence of NAFLD was associated with a more severe CAD, which is bound to have a worse prognosis. Among the limitations of this study are the cross-sectional design and therefore its inability to confirm findings on the rate of CVD events. Moreover, the use of the SS has been mainly validated in the Acute Catheterization and Urgent Intervention Triage StrategY trial only in patients with a non-ST-segment elevation ACS undergoing PCI, and its use in patients with ST elevation ACS might be challenged. Initially, the SS was shown to be an effective tool for predicting the risk of major ischemic events in patients with stable CAD and multivessel or left main disease undergoing PCI, and there are data suggesting a moderate intraobserver reproducibility (its calculation relies on the subjective assessment of lesions using coronary angiography). Nevertheless, the findings of this study are adequate to act as hypothesis generating and should encourage the design of bigger and long-term studies that will prospectively investigate the relationship between the presence and the histological stage of NAFLD with actual midor long-term prognosis of CVD. Moreover, these results might motivate the initiation of interventions to control and, if possible, to reverse the progress of NAFLD from steatosis to a more advanced stage, given that at present time, there is no globally accepted effective intervention for NAFLD. There are some data suggesting a close relationship of NAFLD with the severity of CAD. To begin with, there are very few data on NAFLD and ACS. The most common cause of ACS appears to be vulnerable plaque rupture. These are related to a positive remodeling of the vessel, a large lipid

Association Among Leukocyte Count, Mortality, and Bleeding in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes (from the Acute Catheterization and Urgent Intervention Triage StrategY [ACUITY] Trial)

Although inflammation is involved in the pathogenesis of acute coronary syndromes, the extent of inflammation is not routinely assessed, and its prognostic implications in patients with non-ST-segment elevation acute coronary syndrome have not been investigated in depth. We analyzed the prognostic implications of an elevated white blood cell count (WBCc) in patients with moderate and high-risk non-ST-segment elevation acute coronary syndrome undergoing an early invasive strategy in the large-scale Acute Catheterization and Urgent Intervention Triage StrategY trial. The WBCc at admission was available for 13,678 of 13,819 patients (98.9%). The patients in the upper tertile of the WBCc had an increased risk of 30-day major bleeding, 1-year mortality, and definite/probable stent thrombosis compared to those in the mid or lower tertiles. On multivariate analysis, the WBCc was an independent predictor of 30-day major bleeding and 1-year cardiac, noncardiac, and all-cause mortality. The association between the WBCc and cardiac mortality was present in multiple prespecified subgroups, with no significant interaction between the WBCc and age, gender, diabetes, smoking, renal dysfunction, elevated baseline biomarkers, antithrombotic therapy, revascularization, and Thrombolysis In Myocardial Infarction risk score. The WBCc remained an independent predictor of mortality after adjusting for bleeding, C-reactive protein level, and angiographic variables, including left ventricular ejection fraction, Thrombolysis In Myocardial Infarction flow, and number of diseased vessels. The WBCc significantly improved the prognostic accuracy of the Thrombolysis In Myocardial Infarction risk score, with a net reclassification improvement of 11% (p <0.0001). In conclusion, in patients with moderate- and high-risk non-ST-segment elevation acute coronary syndrome, an elevated admission WBCc was an independent predictor of 30-day major bleeding, and 1-year cardiac, noncardiac, and all-cause mortality.

Complete Revascularization in Contemporary Practice

In patients with acute coronary syndrome (ACS), the pathophysiological process is not limited to a single coronary lesion but involves the entire coronary tree, with 30% to 60% patients presenting with multiple significant coronary lesions, with significant increase in cardiovascular morbidity and mortality in patients with multivessel coronary artery disease.1,2 In the Predictors of Events in the Coronary Tree trial, patients with ACS who underwent percutaneous coronary intervention (PCI), major adverse cardiovascular events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions, which were frequently angiographically mild.3 In contrast, in the COURAGE trial in patients with stable coronary artery disease (CAD) on optimal medical therapy, the only angiographic predictor of future ACS was the number of lesions originally ≥50% that had not been revascularized.4 The above studies attest to the importance of both angiographically significant lesions as well as angiographically mild lesions on future events. These studies highlight the importance of a multipronged approach with the use of evidence-based aggressive medical management (to prevent progression of angiographically mild and also significant CAD), as well as judicious use of optimal revascularization strategies. Several surgical studies have shown that incomplete revascularization in patients undergoing coronary artery bypass graft surgery has worse prognosis with higher mortality, myocardial infarction (MI), and more angina.5–7 As a result, complete anatomic revascularization has become the standard of treatment for coronary artery bypass graft surgery. The concept has been adapted by interventionalist to patients undergoing PCI with several studies (nonrandomized), including an analysis from the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial8 showing substantial increase in cardiovascular events with incomplete revascularization. Similarly, in the Acute Catheterization and Urgent Intervention Triage Strategy trial of patients with nonST-segment elevation ACS, incomplete revascularization …

On-pump versus off-pump surgical revascularization in patients with acute coronary syndromes: Analysis from the Acute Catheterization and Urgent Intervention Triage Strategy trial

Early invasive strategy, defined as early coronary angiography and subsequent revascularization, when appropriate, is recommended by current guidelines for the management of patients with moderate- to high-risk acute coronary syndromes. We sought to compare the outcomes of patients with acute coronary syndromes undergoing surgical revascularization with an on-pump versus off-pump approach. Among a total of 13,819 patients with moderate- to high-risk acute coronary syndromes enrolled in the Acute Catheterization and Urgent Intervention Triage Strategy trial, 1375 patients were triaged to isolated coronary artery bypass grafting. One thousand one hundred fifty-four patients underwent operations with cardiopulmonary bypass (the coronary artery bypass grafting group), and 221 patients underwent off-pump coronary artery bypass grafting (the off-pump coronary artery bypass grafting group). Propensity score matching (1:3) was applied to adjust for differences in baseline clinical and angiographic characteristics, yielding a total of 880 matched patients with acute coronary syndromes (220 managed with off-pump coronary artery bypass grafting and 660 managed with coronary artery bypass grafting). At 30 days, patients undergoing off-pump coronary artery bypass grafting had fewer events of bleeding (43.7% vs 56.3%, P=.0005) and myocardial infarction (7.3% vs 12.1%, P=.055) but higher rates of reintervention (3.7% vs 1.2%, P=.02). At 1 year, there was no difference between groups in death, total myocardial infarctions, reinterventions, strokes, or major adverse cardiac events, but there was a lower rate of non-Q-wave myocardial infarctions in the off-pump coronary artery bypass grafting group (4.6% vs 9.2%, P=.03). In this large-scale study evaluating the outcomes of patients with acute coronary syndromes, off-pump coronary artery bypass grafting was associated with lower rates of bleeding and non-Q-wave myocardial infarction but more reinterventions early after the procedure. At 1 year, there was no major outcome difference between the 2 surgical strategies.

Response to Letter Regarding Article, “Prognostic Modeling of Individual Patient Risk and Mortality Impact of Ischemic and Hemorrhagic Complications: Assessment From the Acute Catheterization and Urgent Intervention Triage Strategy Trial”

We thank Drs De Servi and Navarese for their interest in our study. Their question draws attention to the fact that the causes of death in patients with acute coronary syndromes are multifactorial, due to (1) the acute disease state itself; (2) underlying comorbidities; (3) the success of therapies; and (4) complications arising after initial presentation, either due to the underlying disease or as a consequence of therapeutic interventions. Indeed, as stated in the article,1 only 109 of 524 (21%) deaths in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial occurring by 1 year were attributable to myocardial infarction (MI) or major bleeding. Thus, either a larger sample size, higher baseline mortality rate, or greater proportion of deaths due to the postprocedural complications of ischemia and bleeding would be required for the relative benefits of bivalirudin compared with heparin plus glycoprotein IIb/IIIa inhibitors to result in a statistically significant reduction in mortality. Such a benefit was in fact seen in the Harmonizing Outcomes with Revascularization and Stents …

Letter by De Servi and Navarese Regarding Article, “Prognostic Modeling of Individual Patient Risk and Mortality Impact of Ischemic and Hemorrhagic Complications: Assessment From the Acute Catheterization and Urgent Intervention Triage Strategy Trial”

We read with interest the article by Pocock et al1 on the 1-year prognostic impact of ischemic and hemorrhagic complications in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. Myocardial …

Treating Non–ST-Segment Elevation Acute Coronary Syndromes

0.760, 0.884, and 0.630. In another study of 1728 NSTEACS patients, 7 the c statistics (areas under the curves) for inhospital mortality were 0.68 (95% CI, 0.59 to 0.77), 0.81 (95% CI, 0.73 to 0.89), and 0.80 (95% CI, 0.71 to 0.88), respectively. For 1-year mortality, the c statistics were 0.69 (95% CI, 0.64 to 0.74), 0.79 (95% CI, 0.74 to 0.83), and 0.77 (95% CI, 0.72 to 0.81), respectively. In the present analysis,1 the medically treated patients were stratified using the Thrombolysis in Myocardial Infarction score. The rates of death, myocardial infarction, or unplanned revascularization at 1 year were 4.4%, 7.7%, and 14.3% for patients at low, intermediate, and high risk, respectively. Inclusion of the number of diseased vessels enhanced the ability to predict prognosis beyond the Thrombolysis in Myocardial Infarction risk score, supporting the routine use of angiographic screening in intermediate- to high-risk NSTEACS patients. 1 Although the inclusion criteria of the Acute Catherization and Urgent Intervention Triage Strategy trial targeted intermediate- to high-risk NSTEACS patients, among the medically treated patients in the current analysis whose angiograms were reviewed by the core laboratory,1 26.4% had no significant coronary artery disease. These patients may have been erroneously categorized as having had NSTEACS. Altogether, approximately 1 in 3 patients in the entire Acute Catherization and Urgent Intervention Triage Strategy trial cohort did not undergo any type of revascularization. Some of these patients may have had incidental coronary artery disease, not necessarily NSTEACS. Thus, the angiographic data are initially helpful in deciding whether the patient has NSTEACS, and they then aid in determining the optimal therapy and predicting outcomes. Conversely, given that only 2 in 3 intermediate- to high-risk NSTEACS patients undergo revascularization on the basis of the coronary angiography findings, it may be prudent to obtain angiographic data noninvasively, sparing patients the inherent complications of invasive procedures, and to proceed with invasive coronary angiography and revascularization only in patients with the appropriate findings. Indeed, in the present analysis of medically treated patients who underwent triage angiographically, 3% experienced major bleeding unrelated to bypass surgery, most probably at the access site. An attractive alternative to invasive coronary angiography is multidetector computed tomography of the coronary arteries, which has been shown to aid in the treatment of patients with chest pain of uncertain origin and those with non–high-risk NSTEACS. 8,9 It is not yet recommended for patients with

Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: a risk model from the ACUITY trial

To evaluate the associations of myocardial infarction (MI) and major bleeding with 1-year mortality. Both MI and major bleeding predict 1-year mortality in patients presenting with acute coronary syndrome (ACS). However, the risk of each of these events on the magnitude and timing of mortality has not been well studied. A multivariable Cox regression model was developed relating 13 independent baseline predictors to 1-year mortality for 13 819 patients with moderate and high-risk ACS enrolled in the Acute Catheterization and Urgent Intervention Triage strategy trial. After adjustment for baseline predictors, Cox models with major bleeding and recurrent MI as time-updated covariates estimated the effect of these events on mortality hazard over time. Within 30 days of randomization, 705 patients (5.1%) had an MI, 645 (4.7%) had a major bleed; 524 (3.8%) died within a year. The occurrence of an MI was associated with a hazard ratio of 3.1 compared with patients not yet having an MI, after adjustment for baseline predictors. However, MI within 30 days markedly increased the mortality risk for the first 2 days after the event (adjusted hazard ratio of 17.6), but this risk declined rapidly post-infarct (hazard ratio of 1.4 beyond 1 month after the MI event). In contrast, major bleeding had a prolonged association with mortality risk (hazard ratio of 3.5) which remained fairly steady over time throughout 1 year. After accounting for baseline predictors of mortality, major bleeds and MI have similar overall strength of association with mortality in the first year after ACS. MI is correlated with a dramatic increase in short-term risk, whereas major bleeding correlates with a more prolonged mortality risk.