ISCHEMIA Trial Research Articles

Comparison of risk profiles of participants in the Women's IschemiA TRial to Reduce events In non-ObstRuctive CAD (WARRIOR) trial, using Coronary Computed Tomography Angiography vs Invasive Coronary Angiography

ObjectiveTo compare baseline characteristics of participants in the Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD (WARRIOR) trial by qualification by Coronary Computed Tomography Angiography (CCTA) or Invasive Coronary Angiography (ICA). MethodsThe WARRIOR trial (NCT03417388) is an ongoing multicenter, prospective, randomized, blinded outcome evaluation of intensive medical therapy vs. usual care in women with suspected Ischemia and No Obstructive Coronary Artery Disease (INOCA) identified by either CCTA or ICA on the outcome of major adverse cardiovascular events (MACE). No obstructive coronary artery disease is defined as <50% luminal stenosis and normal coronary arteries is defined as no evidence of atherosclerosis including calcified and non-calcified plaque. Data presented was extracted on May 27, 2020. No clinical outcomes were assessed. ResultsAn initial sample cohort of 797 women was included. The majority were younger than 65 years, White participants (73.3%), 159 had diabetes (19.9%), and 676 had angina (84.8%) with the remainder having symptoms of suspected ischemic heart disease. Over 50% of randomized participants had normal coronaries without luminal irregularities by ICA or CCTA. Participants randomized to ICA were more likely to have worse baseline clinical risk profiles with older age, higher burden of cardiac risk factors and poor quality of life with disabling angina. ConclusionsAmong this initial sample of women with suspected INOCA randomized in the WARRIOR trial, there is a differential baseline cardiac risk of participants enrolled after CCTA or ICA. However, the majority had no evidence of atherosclerotic plaque or obstructive stenosis, after evaluation by ICA or CCTA. These results suggest that non-invasive evaluation with CCTA is likely to be associated with lower risk of MACE.

Reassessing the Role of Ischemia Imaging: Insights from the ISCHEMIA Trial

Reassessing the Role of Ischemia Imaging: Insights from the ISCHEMIA Trial

Does ischaemia testing predict worse adverse outcomes in ANOCA patients?

Abstract Background Following the recent ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) it was revealed that the extent of ischaemia was not associated with an increased risk for adverse outcomes after adjustment for coronary artery disease (CAD) severity. How the extent of ischemia applies to outcomes for patients with stable angina without obstructive CAD is unknown. Purpose To determine if the presence of ischaemia impacted on 3-year clinical outcomes (mortality and readmission) in patients with Angina and Non-Obstructive Coronary Arteries (ANOCA). Methods ANOCA was defined as those presenting with chest pain symptoms consistent with angina and undergoing an elective angiogram. All consecutive ANOCA (stenosis &amp;lt;50%) enrolled in the CADOSA (Coronary Angiogram Database of South Australia) Registry between 2012-2018 were included. CADOSA captures all public hospital patients undergoing coronary angiography. Results Among 8,932 symptomatic patients undergoing elective angiography, 1,169 patients (60±11 years, 59% female) with ANOCA underwent ischaemic stress testing prior to angiography. Of these patients, 185 (16%) had no evidence of ischaemia (ANOCA ischaemia negative), and 984 (84%) had documented evidence of ischaemia (ANOCA ischaemia positive). The ANOCA ischaemic negative patients (relative to the ANOCA ischaemic positive patients) were (a) younger (58±11 vs 61±11, p&amp;lt;0.05), (b) in the year preceding diagnostic angiography, more often presented to the emergency department with chest pain (36% vs 21%, p&amp;lt;0.05) and required hospital admission (28% vs 14%, p&amp;lt;0.05), and (c) had more disabling angina, as assessed by the Canadian Cardiovascular Society Score (CCSS; CCSC-IV 19% vs 13%, p&amp;gt;0.05). At 3-year post-angiography follow-up, (i) cardiac mortality was similar (ANOCA negative 0% vs ANOCA positive 0.1%, p&amp;gt;0.05), but the ANOCA negative patients were more likely to present to the emergency department (26% vs 14%, p&amp;lt; 0.05) and require hospital readmission (18% vs 8%), compared to the ANOCA positive patients. Conclusion Patients with ANOCA and negative ischaemic testing have more disabling symptoms, with frequent emergency department presentations and readmissions, compared to those with a positive ischaemic test. Hence the presence of ischaemia on stress testing is not predictive of clinical outcomes and further investigation is required to identify predictors of outcomes in ANOCA.

Outcomes of Endovascular Treatment for Critical Limb Threatening Ischemia

INTRODUCTIONCritical limb threatening ischemia (CLTI), particularly in patients with ischemic ulceration has been associated with significant morbidity and mortality. Typically, endovascular therapy has been first-line therapy for our patients, but this strategy has come into question based upon the Best Endovascular Versus Best Surgical Therapy in Patients with Critical Limb Threatening Ischemia (BEST-CLI) trial data. METHODS& RESULTS: For comparative purposes, we evaluated outcomes from 150 CLTI patients with ischemic ulceration treated with endovascular-first therapy. The mean age was 72 years in this pre-dominate male, Caucasian, ambulatory group. The major co-morbidities were smoking history in 49% and diabetes mellitus in 67%. Anatomic scoring, using SVS criteria, revealed only 35.6% had favorable anatomy (GLASS of 0,1) for long-term patency compared to 64.4% of limbs with unfavorable anatomy for long-term patency (GLASS 2,3). Stents were used in 47% of cases. Reintervention occurred in 36% over 24 months follow-up. At 12 and 24 months, the Kaplan-Meier projections for survival was 0.80 (0.73, 0.87) and 0.69 (0.59, 0.79); amputation was 0.69 (0.61, 0.77) and 0.59 (0.46, 0.71); amputation-free survival was 0.56 (0.48, 0.65) and 0.38 (0.27, 0.50), respectively. Amputation was more common in those with reinterventions (p=0.033). Mortality was predicted with ABI <0.40 or >1.30 (p=0.0019) and the presence of infection (p=0.0047). Amputation-free survival was predicted by the presence of any infection (p=0.0001). CONCLUSIONDespite technically successful endovascular treatment, patients who present with CLTI maintain a high-risk for limb loss and mortality. Amputation prevention must vigilantly address infection risk. These data correlate with outcomes from BEST-CLI trial enhancing applicability to patient-centered care.

The ISCHEMIA trial revisited: setting the record straight on the benefits of coronary bypass surgery and the misinterpretation of a landmark trial.

The ISCHEMIA trial is a landmark study that has been the subject of heated debate within the cardiovascular community. In this analysis of the ISCHEMIA trial, we aim to set the record straight on the benefits of coronary artery bypass grafting (CABG) and the misinterpretation of this landmark trial. We sought to clarify and reorient this misinterpretation. We herein analyse the ISCHEMIA trial in detail and describe how its misinterpretation has led to an erroneous guideline recommendation downgrading for prognosis-altering surgical therapy in these at-risk patients. The interim ISCHEMIA trial findings align with previous evidence where CABG reduces the long-term risks of myocardial infarction and mortality in advanced coronary artery disease. The trial outcomes of a significantly lower rate of cardiovascular mortality and a higher rate of non-cardiovascular mortality with the invasive strategy are explained according to landmark evidence. The ISCHEMIA trial findings are aligned with previous evidence and should not be used to downgrade recommendations in recent guidelines for the indisputable benefits of CABG.

Current status and perspectives of nuclear cardiology.

Nuclear cardiology has long been used to identify myocardial ischemia for appropriate treatment strategies for stable coronary artery disease (CAD). After the Ischemia Trial, it is time to reevaluate the significance of ischemia assessment. Functional imaging continues to play pivotal role in detecting microcirculatory disturbances. PET provides a clear image of blood flow distribution and is useful for the quantitative evaluation of myocardial flow reserve (MFR), which plays an important role in predicting treatment strategies and improving prognosis in CAD. Heart failure has become a major area of focus in cardiovascular medicine. Radionuclide imaging has been widely applied in this field. FDG PET is useful in identifying cardiac sarcoidosis and active inflammation. Clinical values of I-123 MIBG and BMIPP SPECT have been reported worldwide from Japan. Additionally, clinical experiences of Tc-99m pyrophosphate imaging have recently gained attention for assessing cardiac amyloidosis. Cardiac PET/CT and PET/MR imaging permit combined assessment of metabolic/functional/structural analyses of various cardiac diseases. While other non-invasive imaging modalities have rapidly been developed, the roles of radionuclide imaging remain to be valuable for early and accurate diagnosis and patient management in most cases of chronic CAD and various cardiovascular diseases.

Biomarkers and cardiovascular events in patients with stable coronary disease in the ISCHEMIA Trials

Biomarkers may improve prediction of cardiovascular events for patients with stable coronary artery disease (CAD), but their importance in addition to clinical tests of inducible ischemia and CAD severity is unknown. To evaluate the prognostic value of multiple biomarkers in stable outpatients with obstructive CAD and moderate or severe inducible ischemia. The ISCHEMIA and ISCHEMIA CKD trials randomized 5,956 participants with CAD to invasive or conservative management from July 2012 to January 2018; 1,064 participated in the biorepository. Primary outcome was cardiovascular death, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. Secondary outcome was cardiovascular death or MI. Improvements in prediction were assessed by cause-specific hazard ratios (HR) and area under the receiver operating characteristics curve (AUC) for an interquartile increase in each biomarker, controlling for other biomarkers, in a base clinical model of risk factors, left ventricular ejection fraction (LVEF) and ischemia severity. Secondary analyses were performed among patients in whom core-lab confirmed severity of CAD was ascertained by computed cardiac tomographic angiography (CCTA). Baseline levels of interleukin-6 (IL-6), high sensitivity troponin T (hsTnT), growth differentiation factor 15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP), lipoprotein a (Lp[a]), high sensitivity C-reactive protein (hsCRP), Cystatin C, soluble CD 40 ligand (sCD40L), myeloperoxidase (MPO), and matrix metalloproteinase 3 (MMP3). Among 757 biorepository participants, median (IQR) follow-up was 3 (2-5) years, age was 67 (61-72) years, and 144 (19%) were female; 508 had severity of CAD by CCTA available. In an adjusted multimarker model with hsTnT, GDF-15, NT-proBNP and sCD40L, the adjusted HR for the primary outcome per interquartile increase in each biomarker was 1.58 (95% CI 1.22, 2.205), 1.60 (95% CI 1.16, 2.20), 1.61 (95% 1.22, 2.14), and 1.46 (95% 1.12, 1.90), respectively. The adjusted multimarker model also improved prediction compared with the clinical model, increasing the AUC from 0.710 to 0.792 (P < .01) and 0.714 to 0.783 (P < .01) for the primary and secondary outcomes, respectively. Similar findings were observed after adjusting for core-lab confirmed atherosclerosis severity. Among ISCHEMIA biorepository participants, biomarkers of myocyte injury/distension, inflammation, and platelet activity improved cardiovascular event prediction in addition to risk factors, LVEF, and assessments of ischemia and atherosclerosis severity. These biomarkers may improve risk stratification for patients with stable CAD.

A national analysis of vascular surgery resident operative experience in peripheral artery disease

BackgroundEndovascular and hybrid interventions have played an increasingly prominent role in the treatment of peripheral arterial disease (PAD) in the past decade. This shift has prompted concerns about the adequacy of open surgical training for current surgical residents. Moreover, the recent Best Surgical Therapy in Patients With Critical Limb Ischemia trial has further emphasized the importance of open surgical techniques in the treatment of peripheral arterial disease. The purpose of this study was to examine national temporal trends in peripheral operative volume among integrated vascular surgery residents. MethodsData was obtained from the Accreditation Council for Graduate Medical Education national data reports for integrated vascular surgery residents. Case volumes for surgeon chief or surgeon junior cases were collected from academic years 2012 to 2013 and 2021 to 2022. Trends in case-mix and volume were evaluated using linear regression analysis. ResultsThe mean total vascular operative volume increased from 851.2 to 914.3 cases among graduating chief residents, with an annual growth of 8.5 ± 1.7 cases/year (R2 = 0.77; P < .0001). Major vascular case volume also increased at a rate of 5.7 ± 1.2 cases/year (R2 = 0.74; P < .001). Among operative categories, peripheral cases were the most frequent (n = 232.2 [26.6%]) and demonstrated the greatest annual growth (+8.0 ± 0.8 cases/year, R2 = 0.93; P < .001). No changes were seen in volume of open peripheral cases, including suprainguinal bypass (+0.1 ± 0.2 cases/year; R2 = 0.08; P = .40) or femoropopliteal bypass procedures (−0.1 ± 0.2 cases/year; R2 = 0.17; P = .20). Infrapopliteal bypass (+0.4 ± 0.1 cases/year; R2 = 0.48; P = .006), iliac/femoral endarterectomy (+1.3 ± 0.2 cases/year; R2 = 0.82; P < .001), and leg thromboembolectomy (+0.4 ± 0.1 cases/year; R2 = 0.64; P < .001) all demonstrated annual growth. For endovascular peripheral cases, aortoiliac revascularization (+3.4 ± 0.3 cases/year; R2 = 0.94; P < .001), femoropopliteal revascularization (+5.4 ± 0.2 cases/year; R2 = 0.98; P < .001), and tibioperoneal revascularization (+2.0 ± 0.2 cases/year; R2 = 0.92; P < .001) all increased in volume. Lower extremity amputations, including above-knee amputation (+0.6 ± 0.2 cases/year; R2 = 0.65; P < .001) and below-knee amputation (+0.9 ± 0.2 cases/year; R2 = 0.72; P < .001) also demonstrated an increase in volume. ConclusionsCurrent graduating residents have higher open and endovascular case volumes for peripheral artery disease on a national level, despite the increasing popularity of endovascular techniques. Further studies are needed to identify how these trends may impact current vascular surgery milestones. These trends may also influence the rising interest in competency-based training programs.

Coronary "Microvascular Dysfunction": Evolving Understanding of Pathophysiology, Clinical Implications, and Potential Therapeutics.

Until recently, it has been generally held that stable angina pectoris (SAP) primarily reflects the presence of epicardial coronary artery stenoses due to atheromatous plaque(s), while acute myocardial infarction (AMI) results from thrombus formation on ruptured plaques. This concept is now challenged, especially by results of the ORBITA and ISCHEMIA trials, which showed that angioplasty/stenting does not substantially relieve SAP symptoms or prevent AMI or death in such patients. These disappointing outcomes serve to redirect attention towards anomalies of small coronary physiology. Recent studies suggest that coronary microvasculature is often both structurally and physiologically abnormal irrespective of the presence or absence of large coronary artery stenoses. Structural remodelling of the coronary microvasculature appears to be induced primarily by inflammation initiated by mast cell, platelet, and neutrophil activation, leading to erosion of the endothelial glycocalyx. This leads to the disruption of laminar flow and the facilitation of endothelial platelet interaction. Glycocalyx shedding has been implicated in the pathophysiology of coronary artery spasm, cardiovascular ageing, AMI, and viral vasculitis. Physiological dysfunction is closely linked to structural remodelling and occurs in most patients with myocardial ischemia, irrespective of the presence or absence of large-vessel stenoses. Dysfunction includes the impairment of platelet and vascular responsiveness to autocidal coronary vasodilators, such as nitric oxide, prostacyclin, and hydrogen sulphide, and predisposes both to coronary vasoconstriction and to a propensity for microthrombus formation. These findings emphasise the need for new directions in medical therapeutics for patients with SAP, as well as a wide range of other cardiovascular disorders.

Effects of Elective Coronary Revascularization vs Medical Therapy Alone on Noncardiac Mortality: A Meta-Analysis

BackgroundUncertainty exists whether coronary revascularization plus medical therapy (MT) is associated with an increase in noncardiac mortality in chronic coronary syndrome (CCS) when compared with MT alone, particularly following recent data from the ISCHEMIA-EXTEND (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. ObjectivesThis study conducted a large-scale meta-analysis of trials comparing elective coronary revascularization plus MT vs MT alone in patients with CCS to determine whether revascularization has a differential impact on noncardiac mortality at the longest follow-up. MethodsWe searched for randomized trials comparing revascularization plus MT vs MT alone in patients with CCS. Treatment effects were measured by rate ratios (RRs) with 95% CIs, using random-effects models. Noncardiac mortality was the prespecified endpoint. The study is registered with PROSPERO (CRD42022380664). ResultsEighteen trials were included involving 16,908 patients randomized to either revascularization plus MT (n = 8,665) or to MT alone (n = 8,243). No significant differences were detected in noncardiac mortality between the assigned treatment groups (RR: 1.09; 95% CI: 0.94-1.26; P = 0.26), with absent heterogeneity (I2 = 0%). Results were consistent without the ISCHEMIA trial (RR: 1.00; 95% CI: 0.84-1.18; P = 0.97). By meta-regression, follow-up duration did not affect noncardiac death rates with revascularization plus MT vs MT alone (P = 0.52). Trial sequential analysis confirmed the reliability of meta-analysis, with the cumulative Z-curve of trial evidence within the nonsignificance area and reaching futility boundaries. Bayesian meta-analysis findings were consistent with the standard approach (RR: 1.08; 95% credible interval: 0.90-1.31). ConclusionsIn patients with CCS, noncardiac mortality in late follow-up was similar for revascularization plus MT compared with MT alone.

Long-term follow-up after invasive or conservative management of stable coronary disease: the ISCHEMIA-EXTEND study.

The ISCHEMIA trial found no statistical difference in the primary endpoint between initial invasive and conservative management of patients with chronic coronary disease and moderate-to-severe ischaemia on stress testing. However, an invasive strategy increased peri-procedural myocardial infarction (MI) but decreased spontaneous MI with continued separation of curves over time. Thus, in order to assess the long-term effect of invasive management strategy on mortality, the ISCHEMIA-EXTEND observational study was planned including surviving participants from the initial phase of the ISCHEMIA trial with a projected median follow-up of nearly 10 years. Recently, an interim report of 7-year all-cause, cardiovascular (CV), and non-CV mortality rates has been published showing no difference in all-cause mortality between the two strategies, but with a lower risk of CV mortality and higher risk of non-CV mortality with an initial invasive strategy over a median follow-up of 5.7 years. The trade-offs in CV and non-CV mortality observed in ISCHEMIA-EXTEND raise many important questions regarding the heterogeneity of treatment effect, the drivers of mortality, and the relative importance and reliability of CV vs. all-cause mortality. Overall, findings from ISCHEMIA and ISCHEMIA-EXTEND trials might help physicians in shared decision-making as to whether to add invasive management to guideline-directed medical management in selected patients with chronic coronary artery disease and moderate or severe ischaemia.

Gaps in evidence in recent cardiovascular guidelines: uncertainties in chronic coronary syndrome

The clinical guidelines, while representing an objective reference to perform correct therapeutic choices, contain grey zones, where the recommendations are not supported by solid evidence. In the fifth National Congress Grey Zones held in Bergamo in June 2022, an attempt was made to highlight some of the main grey zones in Cardiology and, through a comparison between experts, to draw shared conclusions that can illuminate our clinical practice. This manuscript contains the statements of the symposium concerning the controversies regarding ischemic cardiomyopathy. The manuscript represents the organization of the meeting, with an initial review of the current guidelines on this topic, followed by an expert presentation of pros (White) and cons (Black) related to the identified "gaps of evidence". For every issue is then reported the "response" derived from the votes of the experts and the public, the discussion and, finally, the highlights, which are intended as practical take home messages to be used in the everyday clinical practice. The first gap in evidence discussed regards the validity of the indication to search for ischemia in light of the data from the ISCHEMIA trial. The second examines the possibility of modifying the algorithm proposed by the European guidelines on anti-ischemic therapy in chronic coronary syndromes. The last gap in evidence evaluates the comparability of long-term antithrombotic strategies in chronic coronary syndromes.

Diabetes, Atherosclerosis, and Stenosis by AI.

This study evaluates the relationship between atherosclerotic plaque characteristics (APCs) and angiographic stenosis severity in patients with and without diabetes. Whether APCs differ based on lesion severity and diabetes status is unknown. We retrospectively evaluated 303 subjects from the Computed TomogRaphic Evaluation of Atherosclerotic Determinants of Myocardial IsChEmia (CREDENCE) trial referred for invasive coronary angiography with coronary computed tomographic angiography (CCTA) and classified lesions as obstructive (≥50% stenosed) or nonobstructive using blinded core laboratory analysis of quantitative coronary angiography. CCTA quantified APCs, including plaque volume (PV), calcified plaque (CP), noncalcified plaque (NCP), low-density NCP (LD-NCP), lesion length, positive remodeling (PR), high-risk plaque (HRP), and percentage of atheroma volume (PAV; PV normalized for vessel volume). The relationship between APCs, stenosis severity, and diabetes status was assessed. Among the 303 patients, 95 (31.4%) had diabetes. There were 117 lesions in the cohort with diabetes, 58.1% of which were obstructive. Patients with diabetes had greater plaque burden (P = 0.004). Patients with diabetes and nonobstructive disease had greater PV (P = 0.02), PAV (P = 0.02), NCP (P = 0.03), PAV NCP (P = 0.02), diseased vessels (P = 0.03), and maximum stenosis (P = 0.02) than patients without diabetes with nonobstructive disease. APCs were similar between patients with diabetes with nonobstructive disease and patients without diabetes with obstructive disease. Diabetes status did not affect HRP or PR. Patients with diabetes had similar APCs in obstructive and nonobstructive lesions. Patients with diabetes and nonobstructive stenosis had an association to similar APCs as patients without diabetes who had obstructive stenosis. Among patients with nonobstructive disease, patients with diabetes had more total PV and NCP.

Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial Ischemia.

Background Sodium-glucose cotransporter-2 inhibitors are cardioprotective independent of glucose control, as demonstrated in animal models of acute myocardial ischemia and clinical trials. The functional and molecular mechanisms of these benefits in the setting of chronic myocardial ischemia are poorly defined. The purpose of this study is to determine the effects of canagliflozin therapy on myocardial perfusion, fibrosis, and function in a large animal model of chronic myocardial ischemia. Methods and Results Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received either no drug (n=8) or 300 mg sodium-glucose cotransporter-2 inhibitor canagliflozin orally, daily (n=8). Treatment continued for 5 weeks, followed by hemodynamic measurements, harvest, and tissue analysis. Canagliflozin therapy was associated with increased stroke volume and stroke work and decreased left ventricular stiffness compared with controls. The canagliflozin group had improved perfusion to ischemic myocardium compared with controls, without differences in arteriolar or capillary density. Canagliflozin was associated with decreased interstitial and perivascular fibrosis in chronically ischemic tissue, with reduced Jak/STAT (Janus kinase/signal transducer and activator of transcription) signaling compared with controls. In ischemic myocardium of the canagliflozin group, there was increased expression and activation of adenosine monophosphate-activated protein kinase, decreased activation of endothelial nitric oxide synthase, and unchanged total endothelial nitric oxide synthase. Canagliflozin therapy reduced total protein oxidation and increased expression of mitochondrial antioxidant superoxide dismutase 2 compared with controls. Conclusions In the setting of chronic myocardial ischemia, canagliflozin therapy improves myocardial function and perfusion to ischemic territory, without changes in collateralization. Attenuation of fibrosis via reduced Jak/STAT signaling, activation of adenosine monophosphate-activated protein kinase, and antioxidant signaling may contribute to these effects.

289 DIAGNOSTIC PATHWAY OF PATIENTS WITH CHRONIC CORONARY SYNDROME AFTER THE ISCHEMIA TRIAL PUBLICATION

Abstract Introduction Patients with chronic coronary syndrome (CCS) can initially undergo an invasive (i.e., early referral to invasive coronary angiography [ICA]) or a conservative (i.e., anatomical or functional testing before ICA) management. The ISCHEMIA trial showed no difference between these two strategies in CCS patients with moderate-to-severe ischemia. The aim of our study was to assess whether the results of the ISCHEMIA trial impacted on the management of CCS patients. Methods Trends in the management of patients with CCS in our centre, according to the ISCHEMIA trial publication date, were analyzed and patients categorized into pre-ISCHEMIA (before March 2020) and post-ISCHEMIA (from July 2020 to February 2022) groups, with an in-between blanking period of three months. The primary outcome was incidence of referral to ICA by coronary computed tomography angiography (CCTA). Secondary objectives included the incidence ischemia test-referred ICA, incidence of CCTA-referred ICA and subsequent percutaneous coronary intervention (PCI), incidence of ischemia test-referred ICA and subsequent PCI and incidence of CCTA-referred ICA without subsequent PCI. Differences between the pre-specified subpopulations (age ≥75 years, diabetes, chronic kidney disease [CKD], peripheral arterial disease [PAD], gender male, unstable angina, active smoking status, body mass index [BMI] &amp;gt;30, hypertension, family history of coronary artery disease [CAD], atrial fibrillation [AF], prior percutaneous coronary intervention [PCI], prior coronary artery bypass grafting [CABG]) and the general population of the study were tested using a regression analysis. Results A total of 2,365 patients were included, 487 (20.6%) and 1,878 (79.4%) in the pre-ISCHEMIA and post-ISCHEMIA groups, respectively. There were no notable between-group differences in baseline characteristics. The primary outcome occurred more frequently in the post-ISCHEMIA group (73.5% vs. 32.5%; p&amp;lt;0.01). Compared to pre-ISCHEMIA, the post-ISCHEMIA group displayed less referrals to ICA by ischemia testing (31.6% vs. 52.5%; p&amp;lt;0.01) and more ICA referrals by CCTA with subsequent PCI (8.3% vs. 12.0%; p&amp;lt;0.01). There were no within-group differences in ischemia test-referred ICA and PCI, and CCTA-referred ICA without subsequent PCI. A regression analysis between the primary endpoint incidence in the general population compared to the incidence in the pre-specified subpopulations showed no significant difference in the p values for interaction. Conclusions In the first two years from publication, the ISCHEMIA trial significantly impacted on the decision-making algorithm for patients with CCS, increasing referral to ICA by CCTA and diminishing ICAs indicated by an ischemia test.

Pathophysiology and Outcomes of Endothelium Function in Coronary Microvascular Diseases: A Systematic Review of Randomized Controlled Trials and Multicenter Study.

Coronary macrovascular disease is a concept that has been well-studied within the literature and has long been the subject of debates surrounding coronary artery bypass grafting (CABG) vs. Percutaneous Coronary Intervention (PCI). ISCHEMIA trial reported no statistical difference in the primary clinical endpoint between initial invasive management and initial conservative management, while in the ORBITA trial PCI did not improve angina frequency score significantly more than placebo, albeit PCI resulted in more patient-reported freedom from angina than placebo. However, these results did not prove the superiority of the PCI against OMT, therefore do not indicate the benefit of PCI vs. the OMT. Please rephrase the sentence. We reviewed the role of different factors responsible for endothelial dysfunction from recent randomized clinical trials (RCTs) and multicentre studies. A detailed search strategy was performed using a dataset that has previously been published. Data of pooled analysis include research articles (human and animal models), CABG, and PCI randomized controlled trials (RCTs). Details of the search strategy and the methods used for data pooling have been published previously and registered with Open-Source Framework. The roles of nitric oxide (NO), endothelium-derived contracting factors (EDCFs), and vasodilator prostaglandins (e.g., prostacyclin), as well as endothelium-dependent hyperpolarization (EDH) factors, are crucial for the maintenance of vasomotor tone within the coronary vasculature. These homeostatic mechanisms are affected by sheer forces and other several factors that are currently being studied, such as vaping. The role of intracoronary testing is crucial when determining the effects of therapeutic medications with further studies on the horizon. The true impact of coronary microvascular dysfunction (CMD) is perhaps underappreciated, which supports the role of medical therapy in determining outcomes. Ongoing trials are underway to further investigate the role of therapeutic agents in secondary prevention.

Predicting left main stenosis in stable ischemic heart disease using logistic regression and boosted trees

BackgroundThe ISCHEMIA trial showed similar cardiovascular outcomes of an initial conservative strategy as compared with invasive management in patients with stable ischemic heart disease without left main stenosis. We aim to assess the feasibility of predicting significant left main stenosis using extensive clinical, laboratory and non-invasive tests data. MethodsAll adult patients who had stress testing prior to undergoing an elective coronary angiography for stable ischemic heart disease in Ontario, Canada, between April 2010 and March 2019, were included. Candidate predictors included comprehensive demographics, comorbidities, laboratory tests, and cardiac stress test data. The outcome was stenosis of 50% or greater in the left main coronary artery. A traditional model (logistic regression) and a machine learning algorithm (boosted trees) were used to build prediction models. ResultsAmong 150,423 patients included (mean age: 64.2 ± 10.6 years; 64.1% males), there were 9,225 (6.1%) with left main stenosis. The final logistic regression model included 24 predictors and 3 interactions, had an optimism-adjusted c-statistic of 0.72 and adequate calibration (optimism-adjusted Integrated Calibration Index 0.0044). These results were consistent in subgroups of males and females, diabetes and non-diabetes, and extent of ischemia. The boosted tree algorithm had similar accuracy, also resulting in a c-statistic of 0.72 and adequate calibration (Integrated Calibration Index 0.0054). ConclusionsIn this large population-based study of patients with stable ischemic heart disease using extensive clinical data, only modest prediction of left main coronary artery disease was possible with traditional and machine learning modelling techniques.

Abstract 13800: Five-Year All-Cause Mortality in the Contemporary Coronary Artery Disease Patients Who Would Be Eligible for ISCHEMIA Trial

Introduction: Landmark ISCHEMIA (ISCH) trial provided unique information, but the generalizability of its results into myocardial revascularization guidelines and practice has been met by unprecedented debate. Hypothesis: We aimed to compare the 5 year all-cause mortality (5y Mt) in our ISCH trial like patients (pts) with results in ISCH. Methods: After applying ISCH study inclusion/exclusion criteria we identified 854 pts from our prospective database of 2455 consecutive pts who had the first isolated CABG in 2012-2015 with complex CAD with 100% follow up (F-up) of 5y Mt. Results: Comparative characteristics of ISCH like and actual ISCH pts are presented in Table 1. Аll our pts underwent CABG, contrary to ISCH where CABG and PCI were used in 538 and 1532 pts, consecutively. Although in ISCH pts had high diversity of ethnicity, were older, had more DM2 (but less insulin dependent), and had previous PCI or CABG in 25%, our pts were strikingly sicker (lower LVEF, higher proportion of 3VD and proximal LAD, higher NYHA as well as more comorbidities) 5-year mortality was 8.9% compared to 9% in the Invasive arm of ISCH. Of note 48 h mortality from MI type 5 (post CABG) was 1.67% in ISCH, and 30-day Mt in our study was 1.30%, with complete revascularization in 95%. As expected by the disease severity treated by CABG early Mt was higher in our than ISCH pts (Figure 1). Conclusion: The present study findings outline that translation of results from the ISCHEMIA trial with practice-changing implications into recommendations for a local Heart Team discussion to advise the best treatment decision for patients with more complex forms of CAD is uncertain and requires further research activities.

Abstract 12499: Anomalous Coronary Arteries Are Associated With Ischemia in the Ischemia Trial

Introduction: Coronary anomalies are detected in 0.3-2.3% of patients undergoing coronary computed tomography angiography (CCTA). Data are scarce on atherosclerosis severity in anomalous arteries and relationship to ischemia on stress testing. Hypothesis: High risk features of anomalous coronary arteries are associated with ischemia, even in the absence of coronary stenosis on CCTA. Methods: 5,903 participants enrolled in the ISCHEMIA trial program with site-determined moderate or severe ischemia underwent CCTA. A core laboratory assessed atherosclerosis severity and made note of anomalous coronary origin. A single reader at the CCTA core laboratory re-evaluated all identified anomalies to assess high risk features and origin, blinded to stress test results. Patients were excluded if stress test results were unavailable. We assessed the relationship between type of anomaly and vessel with ischemia in the subtended territory on stress imaging, and stenosis severity. Results: There was anomalous origin of a coronary artery in 56 of 5,903 CCTA cases (0.9%). Age, sex and CAD risk factors were similar between patients with vs. without anomalies. Anomalous origin affected the left circumflex (LCX) in 28, right coronary artery (RCA) in 21, left main (LM) in 4, and left anterior descending (LAD) in 3. Ischemia was severe on stress testing in 58.2%, moderate in 34.5%, mild in 3.6% and absent in 3.6%. High risk anomalies were present in 17/56 (30.3%, 16/21 RCA and 1/4 LM), including inter-arterial course in 28.6%, intra-mural course in 1.8%, and slit-like orifice in 12.5%. Most anomalous coronaries (82.9%) were associated with ischemia in the subtended territory. Among anomalies associated with ischemia, 37.9% had &lt;50% stenosis and 62.1% had &lt;70% stenosis (Figure). Of those with &lt;70% stenosis, 27.6% had high risk features. Conclusions: Anomalous coronary arteries in stable patients are associated with ischemia, even in the absence of severe atherosclerotic disease.

Comentários sobre o REVIVED-BCIS2 Trial

FINAL CONSIDERATIONS This clinical trial supports the increasingly growing importance of using drug therapy oriented by the most updated guidelines to treat ischemic ventricular dysfunction, regardless of patients being revascularized or not. This had already been demonstrated in the ISCHEMIA trial and, mainly in analysis of subgroups of this study, which enrolled 398 patients with ejection fraction between 35% and 45%, there was a clear benefit of revascularization over OMT after a 4-year follow-up. Other considerations can only be inferred [...]