International Study Of Comparative Health Effectiveness With Medical And Invasive Approaches Research Articles

Outcomes by sex in the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial.

In the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial, among participants with stable coronary artery disease, the risk of cardiac events was similar between an invasive (INV) strategy of angiography and coronary revascularisation and a conservative (CON) strategy of initial medical therapy alone. Outcomes according to participant sex were not reported. We aimed to analyse the outcomes of ISCHEMIA by participant sex. We evaluated 1) the association between participant sex and the likelihood of undergoing revascularisation for participants randomised to the INV arm; 2) the risk of the ISCHEMIA primary composite outcome (cardiovascular death, any myocardial infarction [MI] or rehospitalisation for unstable angina, heart failure or resuscitated cardiac arrest) by participant sex; and 3) the contribution of the individual primary outcome components to the composite outcome by participant sex. Of 5,179 randomised participants, 1,168 (22.6%) were women. Female sex was independently associated with a lower likelihood of revascularisation when assigned to the INV arm (adjusted odds ratio 0.75, 95% confidence interval [CI]: 0.57-0.99; p=0.04). The INV versus CON effect on the primary composite outcome was similar between sexes (women: hazard ratio [HR] 0.96, 95% CI: 0.70-1.33; men: HR 0.90, 95% CI: 0.76-1.07; pinteraction=0.71). The contribution of the individual components to the composite outcome was similar between sexes except for procedural MI, which was significantly lower in women (9/151 [5.9%]) than men (67/519 [12.9%]; p=0.01). In ISCHEMIA, women assigned to the INV arm were less likely to undergo revascularisation than men. The effect of an INV versus CON strategy was consistent by sex, but women had a significantly lower contribution of procedural MI to the primary outcome.

Factors Associated With Coronary Angiography Performed Within 6 Months of Randomization to the Conservative Strategy in the ISCHEMIA Trial.

ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) did not find an overall reduction in cardiovascular events with an initial invasive versus conservative management strategy in chronic coronary disease; however, there were conservative strategy participants who underwent invasive coronary angiography early postrandomization (within 6 months). Identifying factors associated with angiography in conservative strategy participants will inform clinical decision-making in patients with chronic coronary disease. Factors independently associated with angiography performed within 6 months of randomization were identified using Fine and Gray proportional subdistribution hazard models, including demographics, region of randomization, medical history, risk factor control, symptoms, ischemia severity, coronary anatomy based on protocol-mandated coronary computed tomography angiography, and medication use. Among 2591 conservative strategy participants, angiography within 6 months of randomization occurred in 8.7% (4.7% for a suspected primary end point event, 1.6% for persistent symptoms, and 2.6% due to protocol nonadherence) and was associated with the following baseline characteristics: enrollment in Europe versus Asia (hazard ratio [HR], 1.81 [95% CI, 1.14-2.86]), daily and weekly versus no angina (HR, 5.97 [95% CI, 2.78-12.86] and 2.63 [95% CI, 1.51-4.58], respectively), poor to fair versus good to excellent health status (HR, 2.02 [95% CI, 1.23-3.32]) assessed with Seattle Angina Questionnaire, and new/more frequent angina prerandomization (HR, 1.80 [95% CI, 1.34-2.40]). Baseline low-density lipoprotein cholesterol <70 mg/dL was associated with a lower risk of angiography (HR, 0.65 [95% CI, 0.46-0.91) but not baseline ischemia severity nor the presence of multivessel or proximal left anterior descending artery stenosis >70% on coronary computed tomography angiography. Among ISCHEMIA participants randomized to the conservative strategy, angiography within 6 months of randomization was performed in <10% of patients. It was associated with frequent or increasing baseline angina and poor quality of life but not with objective markers of disease severity. Well-controlled baseline low-density lipoprotein cholesterol was associated with a reduced likelihood of angiography. These findings point to the importance of a comprehensive assessment of symptoms and a review of guideline-directed medical therapy goals when deciding the initial treatment strategy for chronic coronary disease. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

Systematic Review of Literature Citing the ISCHEMIA Trial.

Optimal therapy for patients with chronic coronary artery disease (CCD) has long been a topic under investigation and a subject of debate. Seeking to clarify appropriate management, the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial compared medical management versus coronary angiography for patients with stable ischemic heart disease. Its reception in the medical community has been met with both acclaim and criticism. In light of such disparate views of this trial, a systematic review of the literature citing the ISCHEMIA trial was performed. All articles citing the ISCHEMIA trial on PubMed as of July 21, 2023, were compiled and underwent qualitative analysis. A total of 430 articles were evaluated; 109 (25.3%) did not offer substantial commentary on ISCHEMIA and cite it as background evidence for further study. Of the commentary articles, the majority (224, 52.1%) gave balanced, honest appraisals of the ISCHEMIA trial. A total of 46 (10.7%) strongly praised the trial while another 39 (9.1%) were strongly critical of the results. Almost three-quarters of the literature citing the ISCHEMIA trial was commentary in nature, with roughly equal distribution across the spectrum of praise and criticism. Despite being one of the largest studies on CCD and coronary revascularization ever conducted, the impact of ISCHEMIA on the cardiology community appears to be mixed.

Sex Differences in Revascularization, Treatment Goals, and Outcomes of Patients With Chronic Coronary Disease: Insights From the ISCHEMIA Trial.

Women with chronic coronary disease are generally older than men and have more comorbidities but less atherosclerosis. We explored sex differences in revascularization, guideline-directed medical therapy, and outcomes among patients with chronic coronary disease with ischemia on stress testing, with and without invasive management. The ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial randomized patients with moderate or severe ischemia to invasive management with angiography, revascularization, and guideline-directed medical therapy, or initial conservative management with guideline-directed medical therapy alone. We evaluated the primary outcome (cardiovascular death, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest) and other end points, by sex, in 1168 (22.6%) women and 4011 (77.4%) men. Invasive group catheterization rates were similar, with less revascularization among women (73.4% of invasive-assigned women revascularized versus 81.2% of invasive-assigned men; P<0.001). Women had less coronary artery disease: multivessel in 60.0% of invasive-assigned women and 74.8% of invasive-assigned men, and no ≥50% stenosis in 12.3% versus 4.5% (P<0.001). In the conservative group, 4-year catheterization rates were 26.3% of women versus 25.6% of men (P=0.72). Guideline-directed medical therapy use was lower among women with fewer risk factor goals attained. There were no sex differences in the primary outcome (adjusted hazard ratio [HR] for women versus men, 0.93 [95% CI, 0.77-1.13]; P=0.47) or the major secondary outcome of cardiovascular death/myocardial infarction (adjusted HR, 0.93 [95% CI, 0.76-1.14]; P=0.49), with no significant sex-by-treatment-group interactions. Women had less extensive coronary artery disease and, therefore, lower revascularization rates in the invasive group. Despite lower risk factor goal attainment, women with chronic coronary disease experienced similar risk-adjusted outcomes to men in the ISCHEMIA trial. URL: http://wwwclinicaltrials.gov. Unique identifier: NCT01471522.

Outcomes According to Coronary Revascularization Modality in the ISCHEMIA Trial

BackgroundIn the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial, the risk of ischemic events was similar in patients with stable coronary artery disease treated with an invasive (INV) strategy of angiography and percutaneous coronary intervention (PCI) or surgical (coronary artery bypass grafting [CABG]) coronary revascularization and a conservative (CON) strategy of initial medical therapy. ObjectivesThe authors analyzed separately the outcomes of INV patients treated with PCI or CABG. MethodsPatients without preceding primary outcome events were categorized as INV-PCI or INV-CABG from the time of revascularization. The ISCHEMIA primary outcome (composite of cardiovascular death, protocol-defined myocardial infarction or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest) was used. ResultsAmong INV-CABG patients, primary outcome events occurred in 84 of 512 (16.4%) at a median follow-up of 2.85 years; 48 events (57.1%) occurred within 30 days after CABG, including 40 procedural MIs. Among INV-PCI patients, primary outcome events occurred in 147 of 1,500 (9.8%) at median follow-up of 2.94 years; 31 of which (21.1%) occurred within 30 days after PCI, including 24 procedural MIs. In comparison, 352 of 2,591 CON patients (13.6%) had primary outcome events at a median follow-up of 3.2 years, 22 of which (6.3%) occurred within 30 days of randomization. The adjusted primary outcome risks were higher after both CABG and PCI within 30 days (HR: 16.25 [95% CI: 11.44-23.07] and HR: 2.99 [95% CI: 1.97-4.53]) and lower thereafter (0.63 [95% CI: 0.44-0.89] and 0.66 [95% CI: 0.53-0.82]). ConclusionsIn ISCHEMIA, early revascularization by PCI and CABG was associated with higher early risks and lower long-term risks of cardiovascular events compared with CON. The early risk was greatest after CABG, owing to protocol-defined procedural MIs.

Impact of Complete Revascularization in the ISCHEMIA Trial

BackgroundAnatomic complete revascularization (ACR) and functional complete revascularization (FCR) have been associated with reduced death and myocardial infarction (MI) in some prior studies. The impact of complete revascularization (CR) in patients undergoing an invasive (INV) compared with a conservative (CON) management strategy has not been reported. ObjectivesAmong patients with chronic coronary disease without prior coronary artery bypass grafting randomized to INV vs CON management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial, we examined the following: 1) the outcomes of ACR and FCR compared with incomplete revascularization; and 2) the potential impact of achieving CR in all INV patients compared with CON management. MethodsACR and FCR in the INV group were assessed at an independent core laboratory. Multivariable-adjusted outcomes of CR were examined in INV patients. Inverse probability weighted modeling was then performed to estimate the treatment effect had CR been achieved in all INV patients compared with CON management. ResultsACR and FCR were achieved in 43.4% and 58.4% of 1,824 INV patients. ACR was associated with reduced 4-year rates of cardiovascular death or MI compared with incomplete revascularization. By inverse probability weighted modeling, ACR in all 2,296 INV patients compared with 2,498 CON patients was associated with a lower 4-year rate of cardiovascular death or MI (difference −3.5; 95% CI: −7.2% to 0.0%). In comparison, the event rate difference of cardiovascular death or MI for INV minus CON in the overall ISCHEMIA trial was −2.4%. Results were similar but less pronounced with FCR. ConclusionsThe outcomes of an INV strategy may be improved if CR (especially ACR) is achieved. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522)

Complete Revascularization and Angina-Related Health Status in the ISCHEMIA Trial

BackgroundThe impact of complete revascularization (CR) on angina-related health status (symptoms, function, quality of life) in chronic coronary disease (CCD) has not been well studied. ObjectivesAmong patients with CCD randomized to invasive (INV) vs conservative (CON) management in ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), we compared the following: 1) the impact of anatomic and functional CR on health status compared with incomplete revascularization (ICR); and 2) the predicted impact of achieving CR in all INV patients compared with CON. MethodsMultivariable regression adjusting for patient characteristics was used to compare 12-month health status after independent core laboratory-defined CR vs ICR in INV patients who underwent revascularization. Propensity-weighted modeling was then performed to estimate the treatment effect had CR or ICR been achieved in all INV patients, compared with CON. ResultsAnatomic and functional CR were achieved in 43.3% and 57.8% of 1,641 INV patients, respectively. Among revascularized patients, CR was associated with improved Seattle Angina Questionnaire Angina Frequency compared with ICR after adjustment for baseline differences. After modeling CR and ICR in all INV patients, patients with CR and ICR each had greater improvements in health status than CON, with better health status with CR than ICR. The projected benefits of CR were most pronounced in patients with baseline daily/weekly angina and not seen in those with no angina. ConclusionsAmong patients with CCD in ISCHEMIA, health status improved more with CR compared with ICR or CON, particularly in those with frequent angina. Anatomic and functional CR provided comparable improvements in quality of life. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522)

Health Status and Clinical Outcomes in Older Adults With Chronic Coronary Disease: The ISCHEMIA Trial

BackgroundWhether initial invasive management in older vs younger adults with chronic coronary disease and moderate or severe ischemia improves health status or clinical outcomes is unknown. ObjectivesThe goal of this study was to examine the impact of age on health status and clinical outcomes with invasive vs conservative management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. MethodsOne-year angina-specific health status was assessed with the 7-item Seattle Angina Questionnaire (SAQ) (score range 0-100; higher scores indicate better health status). Cox proportional hazards models estimated the treatment effect of invasive vs conservative management as a function of age on the composite clinical outcome of cardiovascular death, myocardial infarction, or hospitalization for resuscitated cardiac arrest, unstable angina, or heart failure. ResultsAmong 4,617 participants, 2,239 (48.5%) were aged <65 years, 1,713 (37.1%) were aged 65 to 74 years, and 665 (14.4%) were aged ≥75 years. Baseline SAQ summary scores were lower in participants aged <65 years. Fully adjusted differences in 1-year SAQ summary scores (invasive minus conservative) were 4.90 (95% CI: 3.56-6.24) at age 55 years, 3.48 (95% CI: 2.40-4.57) at age 65 years, and 2.13 (95% CI: 0.75-3.51) at age 75 years (Pinteraction = 0.008). Improvement in SAQ Angina Frequency was less dependent on age (Pinteraction = 0.08). There were no age differences between invasive vs conservative management on the composite clinical outcome (Pinteraction = 0.29). ConclusionsOlder patients with chronic coronary disease and moderate or severe ischemia had consistent improvement in angina frequency but less improvement in angina-related health status with invasive management compared with younger patients. Invasive management was not associated with improved clinical outcomes in older or younger patients. (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches [ISCHEMIA]; NCT01471522)

Diagnostic and Therapeutic Strategies for Stable Coronary Artery Disease Following the ISCHEMIA Trial.

Until recently, coronary revascularization with coronary artery bypass grafting or percutaneous coronary intervention has been regarded as the standard choice for stable coronary artery disease (CAD), particularly for patients with a significant burden of ischemia. However, in conjunction with remarkable advances in adjunctive medical therapy and a deeper understanding of its long-term prognosis from recent large-scale clinical trials, including ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches), the approach to stable CAD has changed drastically. Although the updated evidence from recent randomized clinical trials will likely modify the recommendations for future clinical practice guidelines, there are still unresolved and unmet issues in Asia, where prevalence and practice patterns are markedly different from those in Western countries. Herein, the authors discuss perspectives on: 1) assessing the diagnostic probability of patients with stable CAD; 2) application of noninvasive imaging tests; 3) initiation and titration of medical therapy; and 4) evolution of revascularization procedures in the modern era.

Abstract 13582: Biomarkers of Adverse Cardiovascular Events in Chronic Coronary Disease: Data From the ISCHEMIA Trial

Introduction: Circulating biomarkers may improve prediction of cardiovascular (CV) events in chronic coronary disease (CCD). The incremental value of biomarkers in CCD after adjustment for clinical factors, inducible ischemia and coronary artery disease (CAD) severity is uncertain. Methods: 756 ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) participants with site-determined moderate-severe ischemia and 9 assayed biomarkers (Figure) were included. Among participants with interpretable stress tests for ischemia and CAD by computed coronary tomography angiography (CCTA) (N=507), associations of biomarkers with the primary (CV death, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest) or secondary endpoints (CV death or MI) were evaluated using sequentially adjusted multivariable Cox proportional hazards models (Model 1=unadjusted, Model 2=clinical features, Model 3=Model 2 + multivessel CAD by CCTA, and Model 4=Model 3 + severe ischemia). Results: Median (IQR) participant age was 64 (57-70) years, 19% were female, 81% white, and 5% Hispanic. Hypertension (85%), diabetes (46%) and obesity (45%) were common, 28% had an estimated glomerular filtration rate &lt;60 ml/min/1.73m 2 . Severe ischemia was present in 44%, and 39% had multivessel CAD (≥70% stenosis) by CCTA. Over 3.5 (2.4-4.7) years of follow-up there were 146 (19%) primary and 128 (17%) secondary endpoints. Soluble CD40L, GDF-15, NT-proBNP, hsTnT were associated with the primary and secondary endpoints in univariable and multivariable (adjusting for clinical features, multivessel CAD and severe ischemia) models. Conclusion: Biomarkers of inflammation (GDF-15), thrombosis (sCD40L), myocardial stretch (NT-proBNP) and injury (hs-troponin) were associated with CV endpoints in the ISCHEMIA trial independent of clinical features, multivessel CAD and severe ischemia.

Abstract 13334: Whole Blood Multi-Omic Characterization of the ISCHEMIA Cohort Reveals Vulnerable and Resilient Subtypes of Chronic Coronary Disease

Introduction: Chronic coronary disease (CCD) is a leading cause of death worldwide. Whole blood (WB) transcriptomic (RNA-seq) and methylation ‘omics’ data can discern molecular underpinnings of CCD and create molecular subtypes to aid risk prediction. Methods: Of 1,064 participants with moderate-severe ischemia (Age: 67.1±6.2, 19.4% Female, 17% non-White) from the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) biorepository, 646 participants had available WB RNA-seq and 737 had WB methylation data ( Fig 1A ). Unsupervised clustering and differential analyses identified omics-derived molecular subtypes. We identified co-regulated gene modules of each subtype, performed subtype-level enrichment of clinical variables, and performed Kaplan-Meier analyses for time to cardiovascular (CV) death or myocardial infarction (MI). Results: Multi-omic analysis revealed 4 RNA-seq-derived subtypes (RS) and 3 methylation-derived subtypes (MS). RNA-seq Subtype 1 (RS1) was enriched for molecular drivers indicative of an adaptive immune response, had clinical enrichment of female sex, statin use, and greater ischemia, and had decreased risk of CV death or MI ( Fig 1B ). RNA-seq Subtype 2 (RS2) was enriched for innate immune response pathway, and patients who were older and White, and was associated with increased risk of CV death or MI. Similarly, methylation subtypes also yielded a high-risk subtype (MS3) and a low-risk subtype (MS2) ( Fig 1C ). Integration of transcriptomic and methylomic subtypes led to further distinction of resilient and vulnerable subgroups. Conclusions: WB RNA-seq and methylation data identified molecularly-defined subtypes that informed the underlying disease pathology of CCD patients in ISCHEMIA. These subgroups were differentially enriched for clinical characteristics and event outcomes, demonstrating the potential use for blood-based omics tests to aid in the prognosis of CCD.

Lessons Learned from the ISCHEMIA Trial for the Management of Patients with Stable Ischemic Heart Disease.

The recent landmark International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial was undertaken to assess whether stable angina patients with moderate to severe baseline ischemia would benefit from an invasive approach with revascularization versus a conservative approach of intensive lifestyle intervention and pharmacologic secondary prevention. This trial addressed the hypothesis that treating ischemia with an invasive approach would reduce major adverse cardiac events more than a noninvasive pharmacologic and lifestyle approach. ISCHEMIA is discussed in detail, along with current implications for contemporary management of this very common cardiac disorder afflicting millions of patients worldwide.

Ischemia With Nonobstructive Coronary Arteries: Insights From the ISCHEMIA Trial

BackgroundIschemia with nonobstructive coronary arteries (INOCA) is common clinically, particularly among women, but its prevalence among patients with at least moderate ischemia and the relationship between ischemia severity and non-obstructive atherosclerosis severity are unknown. ObjectivesThe authors investigated predictors of INOCA in enrolled, nonrandomized participants in ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), sex differences, and the relationship between ischemia and atherosclerosis in patients with INOCA. MethodsCore laboratories independently reviewed screening noninvasive stress test results (nuclear imaging, echocardiography, magnetic resonance imaging or nonimaging exercise tolerance testing), and coronary computed tomography angiography (CCTA), blinded to results of the screening test. INOCA was defined as all stenoses <50% on CCTA in a patient with moderate or severe ischemia on stress testing. INOCA patients, who were excluded from randomization, were compared with randomized participants with ≥50% stenosis in ≥1 vessel and moderate or severe ischemia. ResultsAmong 3,612 participants with core laboratory-confirmed moderate or severe ischemia and interpretable CCTA, 476 (13%) had INOCA. Patients with INOCA were younger, were predominantly female, and had fewer atherosclerosis risk factors. For each stress testing modality, the extent of ischemia tended to be less among patients with INOCA, particularly with nuclear imaging. There was no significant relationship between severity of ischemia and extent or severity of nonobstructive atherosclerosis on CCTA. On multivariable analysis, female sex was independently associated with INOCA (odds ratio: 4.2 [95% CI: 3.4-5.2]). ConclusionsAmong participants enrolled in ISCHEMIA with core laboratory-confirmed moderate or severe ischemia, the prevalence of INOCA was 13%. Severity of ischemia was not associated with severity of nonobstructive atherosclerosis. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522)

Association of Medication Adherence With Health Outcomes in the ISCHEMIA Trial

BackgroundThe ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) trial randomized participants with chronic coronary disease (CCD) to guideline-directed medical therapy with or without angiography and revascularization. The study examined the association of nonadherence with health status outcomes. ObjectivesThe study sought to compare 12-month health status outcomes of adherent and nonadherent participants with CCD with an a priori hypothesis that nonadherent patients would have better health status if randomized to invasive management. MethodsSelf-reported medication-taking behavior was assessed at randomization with a modified 4-item Morisky-Green-Levine Adherence Scale, and participants were classified as adherent or nonadherent. Twelve-month health status was assessed with the 7-item Seattle Angina Questionnaire (SAQ-7) summary score (SS), which ranges from 0 to 100 (higher score = better). The association of adherence with outcomes was evaluated using Bayesian proportional odds models, including an interaction by study arm (conservative vs invasive). ResultsAmong 4,480 randomized participants, 1,245 (27.8%) were nonadherent at baseline. Nonadherent participants had worse baseline SAQ-7 SS in both conservative (72.9 ± 19.3 vs 75.6 ± 18.4) and invasive (71.0 ± 19.8 vs 74.2 ± 18.7) arms. In adjusted analyses, adherence was associated with higher 12-month SAQ-7 SS in both treatment groups (mean difference in SAQ-7 SS with conservative treatment = 1.6 [95% credible interval: 0.3-2.9] vs with invasive management = 1.9 [95% credible interval: 0.8-3.1]), with no interaction by treatment. ConclusionsMore than 1 in 4 participants reported medication nonadherence, which was associated with worse health status in both conservative and invasive treatment strategies at baseline and 12 months. Strategies to improve medication adherence are needed to improve health status outcomes in CCD, regardless of treatment strategy. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522)

Clinical and Quality-of-Life Outcomes Following Invasive vs Conservative Treatment of Patients With Chronic Coronary Disease Across the Spectrum of Kidney Function

Prior trials of invasive vs conservative management of chronic coronary disease (CCD) have not enrolled patients with severe chronic kidney disease (CKD). As such, outcomes across kidney function are not well characterized. To evaluate clinical and quality-of-life (QoL) outcomes across the spectrum of CKD following conservative and invasive treatment strategies. Participants from the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) and ISCHEMIA-Chronic Kidney Disease (CKD) trials were categorized by CKD stage: stage 1 (estimated glomerular filtration rate [eGFR] 90 mL/min/1.73m2 or greater), stage 2 (eGFR 60-89 mL/min/1.73m2), stage 3 (eGFR 30-59 mL/min/1.73m2), stage 4 (eGFR 15-29 mL/min/1.73m2), or stage 5 (eGFR less than 15 mL/min/1.73m2 or receiving dialysis). Enrollment took place from July 26, 2012, through January 31, 2018, with a median follow-up of 3.1 years. Data were analyzed from January 2020 to May 2021. Initial invasive management of coronary angiography and revascularization with guideline-directed medical therapy (GDMT) vs initial conservative management of GDMT alone. The primary clinical outcome was a composite of death or nonfatal myocardial infarction (MI). The primary QoL outcome was the Seattle Angina Questionnaire (SAQ) summary score. Among the 5956 participants included in this analysis (mean [SD] age, 64 [10] years; 1410 [24%] female and 4546 [76%] male), 1889 (32%), 2551 (43%), 738 (12%), 311 (5%), and 467 (8%) were in CKD stages 1, 2, 3, 4, and 5, respectively. By self-report, 18 participants (<1%) were American Indian or Alaska Native; 1676 (29%), Asian; 267 (5%), Black; 861 (16%), Hispanic or Latino; 18 (<1%), Native Hawaiian or Other Pacific Islander; 3884 (66%), White; and 13 (<1%), multiple races or ethnicities. There was a monotonic increase in risk of the primary composite end point (3-year rates, 9.52%, 10.72%, 18.42%, 34.21%, and 38.01% respectively), death, cardiovascular death, MI, and stroke in individuals with higher CKD stages. Invasive management was associated with an increase in stroke (3-year event rate difference, 1%; 95% CI, 0.3 to 1.7) and procedural MI (1.6%; 95% CI, 0.9 to 2.3) and a decrease in spontaneous MI (-2.5%; 95% CI, -3.9 to -1.1) with no difference in other outcomes; the effect was similar across CKD stages. There was heterogeneity of treatment effect for QoL outcomes such that invasive management was associated with an improvement in angina-related QoL in individuals with CKD stages 1 to 3 and not in those with CKD stages 4 to 5. Among participants with CCD, event rates were inversely proportional to kidney function. Invasive management was associated with an increase in stroke and procedural MI and a reduced risk in spontaneous MI, and the effect was similar across CKD stages with no difference in other outcomes, including death. The benefit for QoL with invasive management was not observed in individuals with poorer kidney function.

Outcomes With Intermediate Left Main Disease: Analysis From the ISCHEMIA Trial.

Patients with significant (≥50%) left main disease (LMD) have a high risk of cardiovascular events, and guidelines recommend revascularization to improve survival. However, the impact of intermediate LMD (stenosis, 25%-49%) on outcomes is unclear. Randomized ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) participants who underwent coronary computed tomography angiography at baseline were categorized into those with (25%-49%) and without (<25%) intermediate LMD. The primary outcome was a composite of cardiovascular mortality, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. The primary quality of life outcome was the Seattle Angina Questionnaire summary score. Among the 3699 participants who satisfied the inclusion criteria, 962 (26%) had intermediate LMD. Among invasive strategy participants with intermediate LMD on coronary computed tomography angiography, 49 (7.0%) had significant (≥50% stenosis) left main stenosis on invasive angiography. Patients with intermediate LMD had a higher risk of cardiovascular events in the unadjusted but not in the fully adjusted model compared with those without intermediate LMD. An invasive strategy increased procedural MI and decreased nonprocedural MI with no significant difference for other outcomes including the primary end point. There was no meaningful heterogeneity of treatment effect based on intermediate LMD status except for nonprocedural MI for which there was a greater absolute reduction with invasive management in the intermediate LMD group (-6.4% versus -2.0%; Pinteraction=0.049). The invasive strategy improved angina-related quality of life and the benefit was durable throughout follow-up without significant heterogeneity based on intermediate LMD status. In the ISCHEMIA trial, there was no meaningful heterogeneity of treatment benefit from an invasive strategy regardless of intermediate LMD status except for a greater absolute risk reduction in nonprocedural MI with invasive management in those with intermediate LMD. An invasive strategy increased procedural MI, reduced nonprocedural MI, and improved angina-related quality of life. URL: https://www. gov; Unique identifier: NCT01471522.

Significance of Insignificant Left Main Disease

Significance of Insignificant Left Main Disease

Comprehensive Quality-of-Life Outcomes With Invasive Versus Conservative Management of Chronic Coronary Disease in ISCHEMIA.

ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) compared an initial invasive treatment strategy (INV) with an initial conservative strategy in 5179 participants with chronic coronary disease and moderate or severe ischemia. The ISCHEMIA research program included a comprehensive quality-of-life (QOL) substudy. In 1819 participants (907 INV, 912 conservative strategy), we collected a battery of disease-specific and generic QOL instruments by structured interviews at baseline; at 3, 12, 24, and 36 months postrandomization; and at study closeout. Assessments included angina-related QOL (19-item Seattle Angina Questionnaire), generic health status (EQ-5D), depressive symptoms (Patient Health Questionnaire-8), and, for North American patients, cardiac functional status (Duke Activity Status Index). Median age was 67 years, 19.2% were female, and 15.9% were non-White. The estimated mean difference for the 19-item Seattle Angina Questionnaire Summary score favored INV (1.4 points [95% CI, 0.2-2.5] over all follow-up). No differences were observed in patients with rare/absent baseline angina (SAQ Angina Frequency score >80). Among patients with more frequent angina at baseline (SAQ Angina Frequency score <80, 744 patients, 41%), those randomly assigned to INV had a mean 3.7-point higher 19-item Seattle Angina Questionnaire Summary score than conservative strategy (95% CI, 1.6-5.8) with consistent effects across SAQ subscales: Physical Limitations 3.2 points (95% CI, 0.2-6.1), Angina Frequency 3.2 points (95% CI, 1.2-5.1), Quality of Life/Health Perceptions 5.3 points (95% CI, 2.8-7.8). For the Duke Activity Status Index, no difference was estimated overall by treatment, but in patients with baseline SAQ Angina Frequency scores <80, Duke Activity Status Index scores were higher for INV (3.2 points [95% CI, 0.6-5.7]), whereas patients with rare/absent baseline angina showed no treatment-related differences. Moderate to severe depression was infrequent at randomization (11.5%-12.8%) and was unaffected by treatment assignment. In the ISCHEMIA comprehensive QOL substudy, patients with more frequent baseline angina reported greater improvements in the symptom, physical functioning, and psychological well-being dimensions of QOL when treated with an invasive strategy, whereas patients who had rare/absent angina at baseline reported no consistent treatment-related QOL differences. URL: https://www. gov; Unique identifier: NCT01471522.

Predictors of Left Main Coronary Artery Disease in the ISCHEMIA Trial

BackgroundDetection of ≥50% diameter stenosis left main coronary artery disease (LMD) has prognostic and therapeutic implications. Noninvasive stress imaging or an exercise tolerance test (ETT) are the most common methods to detect obstructive coronary artery disease, though stress test markers of LMD remain ill-defined. ObjectivesThe authors sought to identify markers of LMD as detected on coronary computed tomography angiography (CTA), using clinical and stress testing parameters. MethodsThis was a post hoc analysis of ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches), including randomized and nonrandomized participants who had locally determined moderate or severe ischemia on nonimaging ETT, stress nuclear myocardial perfusion imaging, or stress echocardiography followed by CTA to exclude LMD. Stress tests were read by core laboratories. Prior coronary artery bypass grafting was an exclusion. In a stepped multivariate model, the authors identified predictors of LMD, first without and then with stress testing parameters. ResultsAmong 5,146 participants (mean age 63 years, 74% male), 414 (8%) had LMD. Predictors of LMD were older age (P < 0.001), male sex (P < 0.01), absence of prior myocardial infarction (P < 0.009), transient ischemic dilation of the left ventricle on stress echocardiography (P = 0.05), magnitude of ST-segment depression on ETT (P = 0.004), and peak metabolic equivalents achieved on ETT (P = 0.001). The models were weakly predictive of LMD (C-index 0.643 and 0.684). ConclusionsIn patients with moderate or severe ischemia, clinical and stress testing parameters were weakly predictive of LMD on CTA. For most patients with moderate or severe ischemia, anatomical imaging is needed to rule out LMD. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522)

Post-ISCHEMIA Trial Era: Reconsideration of the Role of Nuclear Cardiology in Patients with Chronic Coronary Artery Disease.

The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial has had a great impact on the management of chronic coronary artery disease (CAD). One of the implications of this trial is the importance of close patient follow-up. To improve patient prognosis, evaluation of the residual extent of ischemia after treatment may be important because several studies have shown a close relationship between residual ischemia and cardiac events. For this assessment, myocardial perfusion single-photon emission computed tomography (MPS) has been utilized and is almost the only modality. Among the participants in the ISCHEMIA trial, more than 10% were excluded due to the absence of obstructive CAD. The pathophysiology of ischemia without non-obstructive coronary artery disease (INOCA) is gaining recognition; however, diagnosis is difficult, except for the assessment of myocardial flow reserve (MFR). Myocardial perfusion positron emission tomography (PET) is the most common modality for noninvasive evaluation of MFR; however, its availability in Japan is limited. For a breakthrough in this situation, a novel gamma camera with a cadmium zinc telluride (CZT) semiconductor might be one of the solutions that enables the evaluation of MFR with a commercially available perfusion tracer, similar to PET. Another solution is a novel PET tracer with a longer half-life. Clinical trials with 18F labeled perfusion agents have been initiated in Japan, and in a few years, delivery of this perfusion tracer will result in more frequent and easier assessment of MFR.