Faculty Bibliography

BACKGROUND/UNASSIGNED:In ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches), an invasive strategy demonstrated better health status outcomes than a conservative strategy in patients with chronic coronary disease (CCD). Some previous studies have shown greater health status benefits with coronary artery bypass grafting (CABG) than percutaneous coronary intervention (PCI). Whether the health status benefits of invasive management in ISCHEMIA were driven primarily by participants treated with CABG is unknown. METHODS/UNASSIGNED:The aim of this analysis was to describe the health status outcomes of participants treated with a conservative strategy (n=2232) compared with invasively managed participants treated with PCI (n=1198) or CABG (n=340) in ISCHEMIA. The Seattle Angina Questionnaire-7 summary score (SAQ-SS) and angina frequency score (SAQ-AF) were the primary outcomes, with higher scores indicating better health status. Proportional odds models comparing 1- and 3-year outcomes were fit, adjusting for demographic, clinical, and angiographic characteristics. RESULTS/UNASSIGNED:SAQ-SS in the conservative, PCI, and CABG groups increased by 9.9±18.1, 15.7±19.3, and 16.1±19.1 points at 1 year and 11.5±20.2, 16.5±21.8, and 15.0±19.4 points at 3 years, respectively. Freedom from angina in the conservative, PCI, and CABG groups was noted in 61.4%, 73.3%, and 82.4% at 1 year and 70.4%, 76.1%, 81.4% at 3 years, respectively. In risk-adjusted analyses, PCI and CABG were each associated with a higher SAQ-SS and SAQ-AF at 1 and 3 years compared with conservative management. SAQ-AF was higher with CABG than PCI at 1 year (odds ratio, 1.54 [95% CI, 1.03, 2.31]), but no differences between CABG and PCI were observed in SAQ-SS (odds ratio, 1.11 [95% CI, 0.78, 1.57]) or SAQ-AF (odds ratio, 0.94 [95% CI, 0.58, 1.54]) at 3 years. CONCLUSIONS/UNASSIGNED:In ISCHEMIA, both PCI and CABG were associated with better 3-year health status than conservative management. Better angina relief with CABG than PCI was seen at 1, but not 3, years. REGISTRATION/UNASSIGNED:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

BACKGROUND:Clinical trials typically report average health status outcomes by treatment at single points in time, as opposed to participants' trajectories (or journeys) over time. Although ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) demonstrated better mean health status at discrete times with an invasive treatment among those with baseline angina, the patterns of individual participants' angina over time are unknown. OBJECTIVES/OBJECTIVE:The purpose of this study was to identify patterns of individual participants' angina over time after invasive or conservative management strategies for chronic coronary disease. METHODS:In this secondary analysis of the ISCHEMIA trial, which enrolled participants with chronic coronary disease and moderate to severe ischemia from July 2012 to January 2018, we used ordinal latent trajectory analysis to assess angina frequency over a 2-year period, separately for participants assigned to the initial invasive and initial conservative arms. Angina frequency was defined using the SAQ-AF (Seattle Angina Questionnaire Angina Frequency) score, recategorized as daily/weekly (0-60 points), monthly (61-99 points), and no angina (100 points). Participants without baseline angina were excluded. RESULTS:Among 2,977 participants with baseline angina, 1,505 (50.6%) were randomized to initial invasive and 1,472 (49.4%) to initial conservative management; baseline characteristics were well balanced between groups. Six distinct patterns of angina trajectories were identified in each arm and were qualitatively similar: 1) rapid resolution; 2) gradual resolution; 3) early improvement with persistent infrequent angina; 4) severe angina with improvement; 5) modest angina with minimal change; and 6) severe angina without improvement. In the invasive group, the most common patterns included rapid resolution (27.1%) and early improvement with persistent infrequent angina (32.1%), whereas the conservative group more often showed modest angina with minimal change (42.1%) and fewer cases of rapid resolution (12.8%) or early improvement with persistent infrequent angina (10.2%). CONCLUSIONS:Patients with chronic coronary disease and angina experienced diverse symptom trajectories, ranging from rapid resolution to severe or persistent angina. A greater proportion of conservatively managed patients experienced unfavorable angina patterns over 2 years compared with those treated invasively. When health status is monitored over time, such patterns may help identify patients with persistent symptoms who could benefit from additional therapy. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

Ischemic heart disease is the leading cause of heart failure with reduced ejection fraction in the developed world. An evolution of background medical therapy over the past decade has spurred improvement in symptoms and a reduction in morbidity and mortality with ischemic cardiomyopathy. However, there is still ongoing debate about the role and impact of revascularization. Much of the societal guidance regarding revascularization with coronary artery bypass grafting in ischemic cardiomyopathy comes from the STICH trial (Surgical Treatment for Ischemic Heart Failure) which predates improvements in medical therapy. More recently, the REVIVED-BCIS2 trial (Revascularization for Ischemic Ventricular Dysfunction-British Cardiovascular Intervention Society) failed to show a benefit of percutaneous coronary intervention on heart failure hospitalization and mortality in ischemic cardiomyopathy over contemporary medical therapy alone. Yet, there are outstanding questions regarding the role and modality of revascularization required to improve outcomes. We review current data and future directions in the management of ischemic cardiomyopathy and the potential role of revascularization.

BACKGROUND:Limited contemporary evidence exists on risk prediction by stress imaging and exercise electrocardiography (ECG) among patients with chronic coronary syndromes (CCS). Objectives From the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) study, prognosis was examined by core laboratory-defined stress imaging and exercise ECG findings in CCS patients. METHODS:A total of 5,179 patients (qualifying by stress nuclear imaging [n = 2,567], echocardiography [n = 1,085], cardiac magnetic resonance [CMR] [n = 257], and ECG [n = 1,270]) were randomized. Cox models assessed associations between trial endpoints and the number of scarred and ischemic segments, rest/stress left ventricular ejection fraction (LVEF), and ST-segment depression. HRs and 95% CIs were calculated per millimeter, segment, or 5% of LVEF. We examined prognostic models for the following trial endpoints: 1) the trial's primary endpoint of cardiovascular (CV) death, myocardial infarction (MI), resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure; 2) CV death; 3) spontaneous MI; 4) procedural MI; and 5) type 2 MI. RESULTS:The number of scarred segments (HR: 1.07 [95% CI: 1.02-1.13]; P = 0.0209), rest LVEF (HR: 0.88 [95% CI: 0.83-0.93]; P < 0.001), and stress LVEF (HR: 0.87 [95% CI: 0.83-0.91]; P < 0.001) predicted the trial's primary endpoint of CV death, MI, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure. The extent of scar and rest/stress LVEF on echocardiography and nuclear imaging predicted several trial endpoints. The number of ischemic segments predicted spontaneous (HR: 1.08 [95% CI: 1.03-1.14]; P = 0.0104) and procedural MI (HR: 1.14 [95% CI: 1.03-1.25]; P = 0.0015) but was of borderline significance for the trial's primary endpoint (P = 0.0746). Ischemia extent by CMR predicted the trial's primary endpoint (P = 0.0068) and spontaneous MI (P = 0.0042). CONCLUSIONS:ISCHEMIA trial findings from 320 worldwide centers revealed that stress imaging and exercise ECG measures exhibited a variable association with key trial endpoints delineating risk patterns for ischemia and infarction. Stress CMR ischemia predicted several trial endpoints, supporting an expanded role in the evaluation of patients with CCS (ISCHEMIA [International Study of Comparative Health Effectiveness With Medical and Invasive Approaches]; NCT01471522).

AIM/OBJECTIVE:To investigate how psychosocial stress contributes to accelerated thrombosis, focusing on platelet activation and hyperreactivity. The specific objective was to identify novel platelet regulators involved in stress-mediated thrombosis, with a particular emphasis on the tetraspanin CD37. METHODS AND RESULTS/RESULTS:To explore how stress contributes to platelet hyperreactivity, platelets were isolated from (1) mice that experienced chronic variable stress and stress-free controls (n=8/group) and (2) human subjects with self-reported high and no stress levels (n=18/group), followed by RNA-sequencing. By comparing mutually expressed transcripts, a subset of genes differentially expressed following psychosocial stress was identified in both human and mouse platelets. In both mice and humans, platelet CD37 positively associates with platelet aggregation responses that underlie thrombosis, with Cd37-/- platelets exhibiting impaired integrin αIIbβ3 signaling, characterized by reduced platelet fibrinogen spreading and decreased agonist-induced αIIbβ3 activation. Consistent with a role for CD37 in regulating platelet activation responses, chimeric mice that received Cd37-/- bone marrow experienced a significantly increased time to vessel occlusion in the carotid artery FeCl3 model compared to mice reconstituted with wild-type bone marrow. CD37 deficiency did not alter hemostasis, as platelet count, coagulation metrics, prothrombin time, and partial thromboplastin time did not differ in Cd37-/- mice relative to wild-type mice. Consistent with this, bleeding time did not differ between wild-type and Cd37-/- mice following tail tip transection. CONCLUSIONS:This study provides new insights into the platelet-associated mechanisms underlying stress-mediated thrombosis. Identifying CD37 as a novel regulator of platelet activation responses offers potential therapeutic targets for reducing the thrombotic risk associated with psychosocial stress. The findings also contribute to understanding how psychosocial stress accelerates thrombotic events and underscore the importance of platelet activation in this process.

BACKGROUND:This study examined stress echocardiography (SE) in relation to coronary artery anatomy, and outcome in subjects randomized in the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) Trial. METHODS:Of 5,179 patients randomized to initial invasive or conservative strategy, SE was performed in 1,079. Coronary computed tomographic angiogram (CCTA) excluded left main disease and quantified coronary lesions. Degree of ischemia was defined by number of segments with stress-induced wall motion abnormalities (WMA) (mild < 3, moderate = 3 and severe > 3). Transient ischemic dilation (TID) was defined as a 10% increase in stress left ventricular (LV) end systolic volume. Primary end point was a composite of cardiovascular death (CVD), nonfatal myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. RESULTS:On CCTA, 607/715 (84%) with CCTA evaluable for ≥70% lesion had one such lesion. Features associated with coronary lesions ≥ 70% were number of ischemic/infarcted segments, 3 or more ischemic segments in the anterior territory and inability to augment LV ejection fraction 10 percentage points . TID, present in 28.5%, was significantly associated with severity of ischemia. For every 0.10 increase in peak wall motion score index (WMSI), there was 12% increased risk of CVD or MI (adjusted HR=1.12 (95% CI: 1.04, 1.21), p=0.003. CONCLUSION/CONCLUSIONS:In patients with chronic coronary disease and moderate or severe myocardial ischemia receiving contemporary therapies, stress echocardiography identified subjects with significant CAD and WMSI provided prognostic value.

BACKGROUND:In the ISCHEMIA Trial, 5179 patients with stable coronary disease were randomized to initial invasive or conservative management. METHODS:PCI was recommended with a SYNTAX score 0-22 (low) and CABG with a SYNTAX score ≥33 (high). Either could be recommended for intermediate scores. The composite primary outcome was cardiovascular death, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. There were two cohorts in this analysis. The descriptive cohort included patients who underwent CABG or PCI within 180 days of randomization and had no primary outcome before revascularization. The comparative cohort excluded participants with prior CABG, single vessel disease, SYNTAX score ≥ 45, and without core laboratory assessment. We focused on the intermediate (23-32) SYNTAX comparative group for which either CABG or PCI could be recommended. RESULTS:For 1935 patients in the descriptive cohort (485 CABG, 1450 PCI), the SYNTAX score was 27.3 ± 11.0 in the CABG group and 15.3 ± 8.6 in the PCI group, p<0.0001. Most patients with low SYNTAX scores underwent PCI (87.1%), while most with high SYNTAX scores underwent CABG (72.6%). For the 1203 patients (385 CABG, 818 PCI) in the entire comparative cohort, the adjusted 4-year primary event rate was 14.5% for CABG and 13.2% for PCI (difference 1.3%, 95% CI, -4.9% to 7.7%). For the 346 patients (163 CABG, 183 PCI) in the intermediate SYNTAX group, the adjusted 4-year primary event rate was 10.6% for CABG and 18.3% for PCI (difference -7.6%, 95% CI, -16.1% to 0.9%). CONCLUSIONS:Selection of revascularization method resulted in more PCI in the low SYNTAX group and more CABG in the high SYNTAX group. There was no statistical evidence of a difference between PCI and CABG in the intermediate SYNTAX group but the CIs are broad, reflecting uncertainty. GOV IDENTIFIER/UNASSIGNED:NCT01471522; https://clinicaltrials.gov/ct2/show/NCT01471522.

BACKGROUND/UNASSIGNED:Therapeutic-dose heparin improves outcomes in noncritically ill patients hospitalized for COVID-19. The effect of antiplatelet exposure in addition to therapeutic-dose heparin is unknown. OBJECTIVES/UNASSIGNED:To evaluate the effect of antiplatelet exposure in addition to therapeutic-dose heparin on survival without organ support. METHODS/UNASSIGNED:We conducted an observational secondary analysis of a multiplatform randomized controlled trial, analyzing noncritically ill patients hospitalized for COVID-19 who received an antiplatelet agent (acetylsalicylic acid or P2Y12 inhibitor) and therapeutic-dose heparin (combination) compared with therapeutic-dose heparin alone (control). We used a 3-level ordinal primary outcome: (1) survival without organ support, (2) survival with organ support, and (3) mortality by day 21. Propensity scores were estimated using logistic regression. Balanced analytic groups were established using stabilized inverse probability of treatment weighting. A proportional odds model was used to estimate the effect of antiplatelet exposure. RESULTS/UNASSIGNED:Among 1021 patients, 194 (19.0%) were exposed to an antiplatelet (95.4% acetylsalicylic acid) and therapeutic-dose heparin. All patients were used to calculate the propensity scores and stabilized weights. After applying inverse probability of treatment weighting, the effective sample size was 60 in the combination group and 652 in the control group. Means and prevalences of continuous and dichotomous variables were similar between groups, with no evidence of misclassification. Exposure to an antiplatelet was not associated with improved survival without organ support (76.3% vs 80.5%; odds ratio, 1.07; 95% CI, 0.71-1.64). CONCLUSION/UNASSIGNED:In noncritically ill patients hospitalized for COVID-19 receiving therapeutic-dose heparin, exposure to an antiplatelet agent was not associated with improved survival without organ support.