Faculty Bibliography

The concept of a direct association between coronary graft patency and clinical status is generally accepted. However, the relationship is more complex and variable than usually thought. Key issues are the lack of a common definition of graft occlusion and of a standardized imaging protocol for patients undergoing coronary bypass surgery. Factors like the type of graft, the timing of the occlusion, and the amount of myocardium at risk, as well as baseline patients' characteristics, modulate the patency-to-clinical status association. Available evidence suggests that graft occlusion is more often associated with non-fatal events rather than death. Also, graft failure due to competitive flow is generally a benign event, while graft occlusion in a graft-dependent circulation is associated with clinical symptoms. In this systematic review, we summarize the evidence on the association between graft status and clinical outcomes.

BACKGROUND:Mechanical circulatory support (MCS) with Impella or intra-aortic balloon pump (IABP) is used for high-risk percutaneous coronary intervention (PCI) and/or for cardiogenic shock (CS) due to acute myocardial infarction. We aimed to investigate the efficacy and safety of Impella or IABP when compared with no MCS using a network meta-analysis of randomized controlled trials (RCTs). METHODS:EMBASE and MEDLINE were searched through February 2020 for RCT evaluating efficacy of Impella vs. IABP vs. no MCS in patients undergoing high-risk PCI or CS. The primary efficacy outcome was 30 day or in-hospital all-cause mortality whereas the primary safety outcomes were major bleeding and vascular complications. RESULTS:= 1.5%). CONCLUSIONS:Neither Impella nor IABP decreased all-cause short-term mortality when compared with no MCS for high-risk PCI and/or CS. Moreover, Impella increased major bleeding compared with no MCS.

A patient with coronavirus disease 19 (COVID-19) developed acute myocardial infarction (AMI) complicated by extensive coronary thrombosis and cardiogenic shock. She underwent percutaneous coronary intervention and placement of a mechanical circulatory support device but subsequently died from shock. This report illustrates the challenges in managing patients with COVID-19, AMI, and cardiogenic shock.

INTRODUCTION/BACKGROUND:Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome. METHODS:The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12-70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30-90 mL/min/1.73 m2, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR. RESULTS:A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was -4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. DISCUSSION/CONCLUSION/CONCLUSIONS:CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.

BACKGROUND:Potent P2Y12 inhibitors reduce cardiovascular events but increase bleeding in patients presenting with acute coronary syndrome (ACS). Elderly patients are at increased risk of bleeding and whether the benefit-risk ratio of potent P2Y12 inhibitors remains favorable is not known. OBJECTIVES/OBJECTIVE:To investigate the efficacy and safety of potent P2Y12 inhibitors versus clopidogrel in elderly patients with ACS. METHODS:PUBMED and EMBASE were searched through July 2020 for randomized control trials (RCTs) or subgroup analyses of RCTs investigating potent P2Y12 inhibitors (prasugrel or ticagrelor) or clopidogrel in elderly (age ≥ 65 years) patients with ACS. The primary outcome was major adverse cardiovascular events (MACE). RESULTS:=0%). In a subgroup analysis, ticagrelor reduced all-cause mortality (HR: 0.73; 95% CI [0.55-0.98]) and cardiovascular death (HR: 0.70; 95% CI [0.54-0.90]) compared with clopidogrel. CONCLUSIONS:Among elderly patients with ACS, potent P2Y12 inhibitors reduce cardiovascular death but increase bleeding with no difference in MACE or all-cause death when compared with clopidogrel. Further RCTs are needed to refine P2Y12 inhibitor selection for elderly patients with ACS.

The number of cardiac surgical meta-analyses and systematic reviews published in the last decades has constantly increased, paralleling the exponential growth observed in virtually all other medical fields. However, meta-analyses are open to methodological flaws if best practices are not strictly followed. Assessment of the appropriateness of the research question is a crucial first step. Once a protocol has been developed, this should be registered before the work is initiated. The cornerstone of any systematic review or meta-analysis is a rigorous, comprehensive, and most of all reproducible search which follows a prespecified and clear strategy. Eligibility criteria must be discussed and agreed upon in advance to guide final study selection, which ultimately lays the foundation for subsequent data extraction. In case of missing or partially reported data, the authors of the original paper should be contacted. Adherence to rigorous methodological rules at each of these stages will warrant availability of good quality data for formal statistical analyses. The aim of the first part of this expert review is to discuss the limits and pitfalls of the meta-analytic approach and provide guidance on how to perform trial level meta-analyses, with particular reference to the identification of an appropriate research question, the definition and registration of the protocol, the search strategy, the study selection and the data abstraction.

In the era of evidence-based medicine, systematic reviews and meta-analyses are considered at the top of evidence hierarchy. Despite the almost exponential increase in the number of published meta-analyses over the course of the last decades, only a small minority of them is of high quality, with major flaws involving every aspect of the meta-analytic process. The strength of a meta-analysis is closely linked to the quality of the included studies. Once preliminary phases are completed, it is vital that selected papers undergo a thorough quality assessment, using the most appropriate tools among those available. Analytical approaches must be tailored to the nature of the extracted data and the specific purpose of the meta-analysis. Appraisal of heterogeneity is a key step to inform subgroup or meta-regression analyses. The solidity of the results of the main analysis (especially in meta-analyses of observational studies or studies with high heterogeneity) should be tested by means of pertinent sensitivity analyses. Finally, the investigators should be aware of the possibility of publication bias and make efforts to assess it using qualitative and quantitative methods. The aim of the second part of this expert review is to provide guidance on how to appropriately perform trial level meta-analyses, with particular focus on the quality assessment of the included studies, the choice of the appropriate statistical approach, the methods to deal with heterogeneity (including subgroup, meta-regression and sensitivity analyses), and the appraisal of publication bias.

Background: In ISCHEMIA, an initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality compared with a conservative strategy in patients with stable ischemic heart disease and moderate/severe myocardial ischemia. The most frequent component of composite cardiovascular endpoints was myocardial infarction. Methods: ISCHEMIA prespecified that the primary and major secondary composite endpoints of the trial be analyzed using two MI definitions. For procedural MI, the primary MI definition used CK-MB as the preferred biomarker whereas the secondary definition used cardiac troponin. Procedural thresholds were >5 times URL for PCI and >10 times for CABG. Procedural MI definitions included (i) a category of elevated biomarker only events with much higher biomarker thresholds (ii) new ST segment depression of ≥ 1mm for the primary and ≥ 0.5 mm for the secondary definition and (iii) new coronary dissections ≥ NHLBI grade 3. We compared MI type, frequency, and prognosis by treatment assignment using both MI definitions. Results: Procedural MI's accounted for 20.1% of all MI events with the primary definition and 40.6% of all MI events with the secondary definition. Four-year MI rates in patients undergoing revascularization were more frequent with the invasive vs conservative strategy using the primary [2.7% vs. 1.1%; adjusted HR 2.98 (95% CI 1.87, 4.73)] and secondary [8.2% vs. 2.0%; adjusted HR 5.04 (95% CI 3.64, 6.97)] MI definitions. Type 1 MI's were less frequent with the invasive vs conservative strategy using the primary [3.40% vs. 6.89%; adjusted HR 0.53 (95% CI 0.41,0.69); p<0.0001], and secondary [3.48% vs 6.89%; adjusted HR 0.53 (95% CI 0.41, 0.69); p<0.0001] definitions. The risk of subsequent cardiovascular death was higher after a type 1 MI compared to no MI using the primary [adjusted HR 3.38 (95% CI 2.03,5.61); p<0.001] or secondary MI definition [adjusted HR 3.52 (2.11, 5.88); p<0.001]. Conclusions: In ISCHEMIA, type 1 MI events using the primary and secondary definitions during 5-year follow-up were more frequent with an initial conservative strategy and associated with subsequent cardiovascular death. Procedural MI rates were greater in the invasive strategy and using the secondary MI definition. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT01471522.

Background: Myocardial infarction with non-obstructive coronary arteries (MINOCA) occurs in 6-15% of MI and disproportionately affects women. Scientific statements recommend multi-modality imaging in MINOCA to define the underlying cause. We performed coronary optical coherence tomography (OCT) and cardiac magnetic resonance imaging (CMR) to assess mechanisms of MINOCA. Methods: In this prospective, multicenter, international, observational study, we enrolled women with a clinical diagnosis of MI. If invasive coronary angiography revealed <50% stenosis in all major arteries, multi-vessel OCT was performed, followed by CMR (cine imaging, late gadolinium enhancement, and T2-weighted imaging and/or T1 mapping). Angiography, OCT, and CMR were evaluated at blinded, independent core laboratories. Culprit lesions identified by OCT were classified as definite or possible. The CMR core laboratory identified ischemia-related and non-ischemic myocardial injury. Imaging results were combined to determine the mechanism of MINOCA, when possible. Results: Among 301 women enrolled at 16 sites, 170 were diagnosed with MINOCA, of whom 145 had adequate OCT image quality for analysis; 116 of these underwent CMR. A definite or possible culprit lesion was identified by OCT in 46.2% (67/145) of participants, most commonly plaque rupture, intra-plaque cavity or layered plaque. CMR was abnormal in 74.1% (86/116) of participants. An ischemic pattern of CMR abnormalities (infarction or myocardial edema in a coronary territory) was present in 53.4% of participants undergoing CMR (62/116). A non-ischemic pattern of CMR abnormalities (myocarditis, takotsubo syndrome or non-ischemic cardiomyopathy) was present in 20.7% (24/116). A cause of MINOCA was identified in 84.5% of the women with multi-modality imaging (98/116), higher than with OCT alone (p<0.001) or CMR alone (p=0.001). An ischemic etiology was identified in 63.8% of women with MINOCA (74/116), a non-ischemic etiology was identified in 20.7% (24/116), and no mechanism was identified in 15.5% (18/116). Conclusions: Multi-modality imaging with coronary OCT and CMR identified potential mechanisms in 84.5% of women with a diagnosis of MINOCA, three-quarters of which were ischemic and one-quarter of which were non-ischemic, alternate diagnoses to MI. Identification of the etiology of MINOCA is feasible and has the potential to guide medical therapy for secondary prevention. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02905357.