Faculty Bibliography

Importance/UNASSIGNED:It is unknown whether coronary revascularization, when added to optimal medical therapy, improves prognosis in patients with stable ischemic heart disease (SIHD) at increased risk of cardiovascular events owing to moderate or severe ischemia. Objective/UNASSIGNED:To describe baseline characteristics of participants enrolled and randomized in the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial and to evaluate whether qualification by stress imaging or nonimaging exercise tolerance test (ETT) influenced risk profiles. Design, Setting, and Participants/UNASSIGNED:The ISCHEMIA trial recruited patients with SIHD with moderate or severe ischemia on stress testing. Blinded coronary computed tomography angiography was performed in most participants and reviewed by a core laboratory to exclude left main stenosis of at least 50% or no obstructive coronary artery disease (CAD) (<50% for imaging stress test and <70% for ETT). The study included 341 enrolling sites (320 randomizing) in 38 countries and patients with SIHD and moderate or severe ischemia on stress testing. Data presented were extracted on December 17, 2018. Main Outcomes and Measures/UNASSIGNED:Enrolled, excluded, and randomized participants' baseline characteristics. No clinical outcomes are reported. Results/UNASSIGNED:A total of 8518 patients were enrolled, and 5179 were randomized. Common reasons for exclusion were core laboratory determination of insufficient ischemia, unprotected left main stenosis of at least 50%, or no stenosis that met study obstructive CAD criteria on study coronary computed tomography angiography. Randomized participants had a median age of 64 years, with 1168 women (22.6%), 1726 nonwhite participants (33.7%), 748 Hispanic participants (15.5%), 2122 with diabetes (41.0%), and 4643 with a history of angina (89.7%). Among the 3909 participants randomized after stress imaging, core laboratory assessment of ischemia severity (in 3901 participants) was severe in 1748 (44.8%), moderate in 1600 (41.0%), mild in 317 (8.1%) and none or uninterpretable in 236 (6.0%), Among the 1270 participants who were randomized after nonimaging ETT, core laboratory determination of ischemia severity (in 1266 participants) was severe (an eligibility criterion) in 1051 (83.0%), moderate in 101 (8.0%), mild in 34 (2.7%) and none or uninterpretable in 80 (6.3%). Among the 3912 of 5179 randomized participants who underwent coronary computed tomography angiography, 79.0% had multivessel CAD (n = 2679 of 3390) and 86.8% had left anterior descending (LAD) stenosis (n = 3190 of 3677) (proximal in 46.8% [n = 1749 of 3739]). Participants undergoing ETT had greater frequency of 3-vessel CAD, LAD, and proximal LAD stenosis than participants undergoing stress imaging. Conclusions and Relevance/UNASSIGNED:The ISCHEMIA trial randomized an SIHD population with moderate or severe ischemia on stress testing, of whom most had multivessel CAD. Trial Registration/UNASSIGNED:ClinicalTrials.gov Identifier: NCT01471522.

Cardiogenic shock occurs in up to 5% to 10% of acute myocardial infarctions(MI) and is associated with high short- and long-term mortality risk. Since its introduction into clinical practice >50 years ago, intra-aortic balloon counterpulsion has been used empirically to provide hemodynamic support in patients undergoing coronary revascularization in the setting of MI and cardiogenic shock. In the landmark SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial, conducted between 1993 and 1998, intra-aortic balloon pumps (IABP) were placed in 86% of participants, irrespective of the assigned management strategy.¹ Although expert opinion supported clinical benefit of IABP use in cardiogenic shock, the first large randomized, multi-center trial of IABP, published in 2012, upended this conventional wisdom. The IABP-SHOCK II(Intra-aortic Balloon Pump in Cardiogenic Shock II) trial randomly assigned 600 participants planned for early revascularization of acute MI complicated by cardiogenic shock to either IABP placement or no IABP placement.² The primary end point was 30-day all-cause mortality. At 30 days, all-cause mortality was 40%, with no difference between patients randomized to receive an IABP versus those who were not. There were no differences between treatment groups in secondary outcomes, including bleeding, ischemic complications, stroke, time to hemodynamic stabilization, intensive care unit length of stay, and the dose and duration of catecholamine therapy. A previous intermediate-term report of IABP-SHOCK II trial outcomes demonstrated no difference between treatment groups for allcause mortality at 12 months.³ In this issue of Circulation, Thiele et al⁴ report the 6-year results of the IABPSHOCK II randomized trial. At 6 years of follow-up, all-cause mortality was high and did not differ between the IABP and control groups (66.3% versus 67.0%) in intention-to-treat, per-protocol, and as-treated analyses. No signal for benefit associated with IABP use was observed in any prespecified or post hoc subgroups. There were no differences in the frequency of recurrent MI, repeat revascularization, stroke, or cardiovascular rehospitalization between the 2 groups. Quality of life, measured by the EuroQol 5D questionnaire and New York Heart Association classification, was favorable in survivors of cardiogenic shock. Four of 5 survivors had New York Heart Association Class I or II symptoms, with no difference between patients randomly assigned to IABP and no IABP therapy.

BACKGROUND AND AIMS/OBJECTIVE:Platelets are a major culprit in the pathogenesis of cardiovascular disease (CVD). Circulating monocyte-platelet aggregates (MPA) represent the crossroads between atherothrombosis and inflammation. However, there is little understanding of the platelets and monocytes that comprise MPA and the prevalence of MPA in different CVD phenotypes. We aimed to establish (1) the reproducibility of MPA over time in circulating blood samples from healthy controls, (2) the effect of aspirin, (3) the relationship between MPA and platelet activity and monocyte subtype, and (4) the association between MPA and CVD phenotype (coronary artery disease, peripheral artery disease [PAD], abdominal aortic aneurysm, and carotid artery stenosis). METHODS AND RESULTS/RESULTS:platelets in healthy subjects and in patients with CVD. We found that MPA did not significantly differ over time in healthy controls, nor altered by aspirin use. Compared with healthy controls, MPA were significantly higher in CVD (9.4% [8.2, 11.1] vs. 21.8% [11.5, 44.1], p < 0.001) which remained significant after multivariable adjustment (β = 9.1 [SER = 3.9], p = 0.02). We found PAD to be associated with a higher MPA in circulation (β = 19.3 [SER = 6.0], p = 0.001), and among PAD subjects, MPA was higher in subjects with critical limb ischemia (34.9% [21.9, 51.15] vs. 21.6% [15.1, 40.6], p = 0.0015), and significance remained following multivariable adjustment (β = 14.77 (SE = 4.35), p = 0.001). CONCLUSIONS:Circulating MPA are a robust marker of platelet activity and monocyte inflammation, unaffected by low-dose aspirin, and are significantly elevated in subjects with CVD, particularly those with PAD.

The Principal INvestigator Development and Resources (PINDAR) program was developed at the NYU-H+H Clinical and Translational Science Award (CTSA) hub in response to a perceived need for focused good clinical practice (GCP) training designed specifically for principal investigators (PIs) performing human subject research. PINDAR is a novel 6-hour, instructor lead, participatory, in-person course for PIs developed de novo, piloted, and implemented. One hundred and seventeen faculty PIs participated in PINDAR from November 2016 through September 2018. All obtained mutual recognition for ICH E6 GCP training from TransCelerate Biopharma. PINDAR was well received by participant PIs, and feedback surveys have revealed a high degree of satisfaction with the program. Other CTSA hubs and research-intensive health systems should consider adopting a similar course focused on GCP for PIs.

OBJECTIVES/OBJECTIVE:The aim of this study was to determine whether frailty is associated with increased bleeding risk in the setting of acute myocardial infarction (AMI). BACKGROUND:Frailty is a common syndrome in older adults. METHODS:Frailty was examined among AMI patients ≥65 years of age treated at 775 U.S. hospitals participating in the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry from January 2015 to December 2016. Frailty was classified on the basis of impairments in 3 domains: walking (unassisted, assisted, wheelchair/nonambulatory), cognition (normal, mildly impaired, moderately/severely impaired), and activities of daily living. Impairment in each domain was scored as 0, 1, or 2, and a summary variable consisting of 3 categories was then created: 0 (fit/well), 1 to 2 (vulnerable/mild frailty), and 3 to 6 (moderate-to-severe frailty). Multivariable logistic regression was used to examine the independent association between frailty and bleeding. RESULTS:Among 129,330 AMI patients, 16.4% had any frailty. Frail patients were older, more often female, and were less likely to undergo cardiac catheterization. Major bleeding increased across categories of frailty (fit/well 6.5%; vulnerable/mild frailty 9.4%; moderate-to-severe frailty 9.9%; p < 0.001). Among patients who underwent catheterization, both frailty categories were independently associated with bleeding risk compared with the non-frail group (vulnerable/mild frailty adjusted odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.23 to 1.44; moderate-to-severe frailty adjusted OR: 1.40, 95% CI: 1.24 to 1.58). Among patients managed conservatively, there was no association of frailty with bleeding (vulnerable/mild frailty adjusted OR: 1.01, 95% CI: 0.86 to 1.19; moderate-to-severe frailty adjusted OR: 0.96, 95% CI: 0.81 to 1.14). CONCLUSIONS:Frail patients had lower use of cardiac catheterization and higher risk of major bleeding (when catheterization was performed) than nonfrail patients, making attention to clinical strategies to avoid bleeding imperative in this population.

BACKGROUND:Patients with chronic kidney disease (CKD) and stable ischemic heart disease are at markedly increased risk of cardiovascular events. Prior trials comparing a strategy of optimal medical therapy (OMT) with or without revascularization have largely excluded patients with advanced CKD. Whether a routine invasive approach when compared with a conservative strategy is beneficial in such patients is unknown. METHODS:or on dialysis) and moderate or severe ischemia on stress testing. Participants were randomized in a 1:1 fashion to the invasive or a conservative strategy. The primary end point is a composite of death or nonfatal myocardial infarction. Major secondary endpoints are a composite of death, nonfatal myocardial infarction, hospitalization for unstable angina, hospitalization for heart failure, or resuscitated cardiac arrest; angina control; and disease-specific quality of life. Safety outcomes such as initiation of maintenance dialysis and a composite of initiation of maintenance dialysis or death will be reported. The trial is projected to have 80% power to detect a 22% to 24% reduction in the primary composite end point with the invasive strategy when compared with the conservative strategy. CONCLUSIONS:ISCHEMIA-CKD will determine whether an initial invasive management strategy improves clinical outcomes when added to OMT in patients with advanced CKD and stable ischemic heart disease.