Faculty Bibliography

BACKGROUND:The optimal duration of hemostatic compression post transradial access is controversial. Longer duration increases the risk of radial artery occlusion (RAO) while shorter duration increases the risk of access site bleeding or hematoma. As such, a target of 2 hours is typically used. Whether a shorter or longer duration is better is not known. METHODS:A PubMed, EMBASE, and clinicaltrials.gov databases were searched for randomized clinical trials of different duration (<90 minutes, 90 minutes, 2 hours, and 2-4 hours) of hemostasis banding. The efficacy outcome was RAO, primary safety outcome was access site hematoma, and secondary safety outcome was access site rebleeding. Primary analysis compared the effect of various duration in reference to the 2 hours duration using a mixed treatment comparison meta-analysis. RESULTS:Of the 10 randomized clinical trials included with 4911 patients, when compared to the 2-hour reference duration, there was a significantly higher risk of access site hematoma with 90 minutes (odds ratio, 2.39 [95% CI, 1.40-4.06]) and <90 minutes (odds ratio, 3.61 [95% CI, 1.79-7.29]) but not with the 2 to 4 hours duration. When compared with the 2-hour reference, there was no significant difference in access site rebleeding or RAO with shorter or longer duration but the point estimates favored longer duration for access site rebleeding and shorter duration for RAO. Duration of <90 minutes and 90 minutes ranked 1 and duration of 2 hours ranked 2 as the most efficacious duration whereas duration of 2 hours ranked 1 and 2 to 4 hours ranked 2 as the safest duration. CONCLUSIONS:In patients undergoing transradial access for coronary angiography or intervention, a hemostasis duration of 2 hours offers the best balance for efficacy (prevention of RAO) and safety (prevention of access site hematoma/rebleeding).

BACKGROUND:The role of percutaneous coronary interventions (PCI) in patients with diabetes mellitus and multi-vessel disease has been questioned by the results of the FREEDOM trial, which showed superiority of coronary artery bypass graft(CABG) over first generation drug-eluting stents (DES) including a reduction in mortality. In the light of safer and more efficacious stents and significantly better medical management, those results that date back to 2012 need to be revisited. TUXEDO-2 is a study designed to compare two contemporary stents in Indian diabetic patients with multi-vessel disease. AIMS:The primary objective of the TUXEDO-2 study is to compare the clinical outcomes of PCI with ultra-thin Supraflex Cruz vs Xience when combined with contemporary optimal medical therapy (OMT) in diabetic patients with multi-vessel disease. The secondary objective is to compare clinical outcomes between a pooled cohort from both arms of the study (Supraflex Cruz + Xience; PCI arm) vs CABG based on a performance goal derived from the CABG arm of the FREEDOM trial (historical cohort). The tertiary objective is a randomized comparison of ticagrelor vs prasugrel in addition to aspirin for the composite of ischemic and bleeding events. METHODS:In this prospective, open-label, multi-centre, 2 × 2 factorial, randomized, controlled study, 1,800 patients with diabetes mellitus and multi-vessel disease (inclusion criteria similar to FREEDOM trial) with indication for coronary revascularization will be randomly assigned to Supraflex Cruz or Xience stents and also to ticagrelor- or prasugrel- based antiplatelet strategies. All patients will receive guideline directed OMT and optimal PCI including image- and physiology-guided complete revascularization where feasible. The patients will be followed through five years to assess their clinical status and major clinical events. The primary endpoint is a non-inferiority comparison of target lesion failure at one-year for Supraflex Cruz vs Xience (primary objective) with an expected event rate of 11% and a non-inferiority margin of 4.5%. For PCI vs CABG (secondary objective), the primary endpoint is major adverse cardiac events (MACE), defined as a composite of all cause death, nonfatal myocardial infarction, or stroke at one-year and yearly up to five years, with a performance goal of 21.6%. For ticagrelor vs prasugrel (tertiary objective), the primary endpoint is composite of death, myocardial infarction, stroke, and major bleeding as per the Bleeding Academic Research Consortium (BARC) at one-year with expected event rate of 15% and a non-inferiority margin of 5%. CONCLUSIONS:The TUXEDO-2 study is a contemporary study involving state-of-the-art PCI combined with guideline directed OMT in a complex subset of patients with diabetes mellitus and multi-vessel disease. The trial will answer the question as to whether a biodegradable polymer coated ultra-thin Supraflex Cruz stent is an attractive option for PCI in diabetic patients with multi-vessel disease. It will also help address the question whether the results of FREEDOM trial would have been different in the current era of safer and more efficacious stents and modern medical therapy. In addition, the comparative efficacy and safety of ticagrelor vs prasugrel in addition to aspirin will be evaluated. (CTRI/2019/11/022088).

BACKGROUND/UNASSIGNED:The optimal revascularization approach in patients with heart failure with reduced ejection fraction (HFrEF) and ischemic heart disease ("ischemic cardiomyopathy") is unknown. Physician preferences regarding clinical equipoise for mode of revascularization and their willingness to consider offering enrollment in a randomized trial to patients with ischemic cardiomyopathy have not been characterized. METHODS/UNASSIGNED:We conducted two anonymous online surveys: 1) a clinical case scenario-based survey to assess willingness to offer clinical trial enrollment for a patient with ischemic cardiomyopathy (overall response rate to email invitation 0.45 %), and 2) a Delphi consensus-building survey to identify specific areas of clinical equipoise (overall response rate to email invitation 37 %). RESULTS/UNASSIGNED:< 0.0001). In 17 scenarios (11.8 %), there was no difference in CABG or PCI appropriateness ratings, suggesting clinical equipoise in these settings. CONCLUSIONS/UNASSIGNED:Our findings demonstrate willingness to consider offering enrollment in a randomized clinical trial and areas of clinical equipoise, two factors that support the feasibility of a randomized trial to compare clinical outcomes after revascularization with CABG vs. PCI in selected patients with ischemic cardiomyopathy, suitable coronary anatomy and co-morbidity profile.

BACKGROUND:In ISCHEMIA-CKD, 777 patients with advanced chronic kidney disease and chronic coronary disease had similar all-cause mortality with either an initial invasive or conservative strategy (27.2% vs 27.8%, respectively). OBJECTIVES/OBJECTIVE:This prespecified secondary analysis from ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) was conducted to determine whether an initial invasive strategy compared with a conservative strategy decreased the incidence of cardiovascular (CV) vs non-CV causes of death. METHODS:Three-year cumulative incidences were calculated for the adjudicated cause of death. Overall and cause-specific death by treatment strategy were analyzed using Cox models adjusted for baseline covariates. The association between cause of death, risk factors, and treatment strategy were identified. RESULTS:A total of 192 of the 777 participants died during follow-up, including 94 (12.1%) of a CV cause, 59 (7.6%) of a non-CV cause, and 39 (5.0%) of an undetermined cause. The 3-year cumulative rates of CV death were similar between the invasive and conservative strategies (14.6% vs 12.6%, respectively; HR: 1.13, 95% CI: 0.75-1.70). Non-CV death rates were also similar between the invasive and conservative arms (8.4% and 8.2%, respectively; HR: 1.25; 95% CI: 0.75-2.09). Sudden cardiac death (46.8% of CV deaths) and infection (54.2% of non-CV deaths) were the most common cause-specific deaths and did not vary by treatment strategy. CONCLUSIONS:In ISCHEMIA-CKD, CV death was more common than non-CV or undetermined death during the 3-year follow-up. The randomized treatment assignment did not affect the cause-specific incidences of death in participants with advanced CKD and moderate or severe myocardial ischemia. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease [ISCHEMIA-CKD]; NCT01985360).

BACKGROUND:Ischemia 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. OBJECTIVES/OBJECTIVE:The 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. METHODS:Core 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. RESULTS:Among 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, women female sex was independently associated with INOCA (odds ratio: 4.2 [95% CI: 3.4-5.2]). CONCLUSIONS:Among 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).

The increase of intravenous drug use has led to an increase in right-sided infective endocarditis and its complications including septic pulmonary embolism. The objective of this study was to compare the outcomes of tricuspid valve (TV) operations in patients with drug-use infective endocarditis (DU-IE) complicated by septic pulmonary emboli (PE). Hospitalizations for DU-IE complicated by septic PE were identified from the National Inpatient Sample from 2002 to 2019. Outcomes of patients who underwent TV operations were compared with medical management. The primary outcome was the incidence of major adverse cardiovascular events (MACEs), defined as in-hospital mortality, myocardial infarction, stroke, cardiogenic shock, or cardiac arrest. An inverse probability of treatment weighted analysis was utilized to adjust for the differences between the cohorts. A total of 9,029 cases of DU-IE with septic PE were identified (mean age 33.6 years), of which 818 patients (9.1%) underwent TV operation. Surgery was associated with a higher rate of MACE (14.5% vs 10.8%, p <0.01), driven by a higher rate of cardiogenic shock (6.1% vs 1.2%, p <0.01) but a lower rate of mortality (2.7% vs 5.7%, p <0.01). Moreover, TV operation was associated with an increased need for permanent pacemakers, blood transfusions, and a higher risk of acute kidney injury. In the inverse probability treatment weighting analysis, TV operation was associated with an increased risk for MACE driven by a higher rate of cardiogenic shock and cardiac arrest, but a lower rate of mortality when compared with medical therapy alone. In conclusion, TV operations in patients with DU-IE complicated by septic PE are associated with an increased risk for MACE but a decreased risk of mortality. Although surgical management may be beneficial in some patients, alternative options such as percutaneous debulking should be considered given the higher risk.

OBJECTIVE:To compare rates of clopidogrel response among patients receiving medication produced by 2 different manufacturers after acute coronary syndrome (ACS) and/or percutaneous coronary intervention. METHODS:This quality-improvement project included 515 adult patients receiving clopidogrel for ACS or ischemic heart disease and referred for coronary angiography/ percutaneous coronary intervention. The project was divided into 2 phases: (1) retrospective collection of baseline data (April 2019-October 2020); and (2) two 12-week, prospective phases in which all clopidogrel in the hospital was restricted to a single manufacturer at a time (November 2020-May 2021). The primary outcome was clopidogrel response measured by platelet function testing, defined as adenosine diphosphate (ADP) response <40% on light transmission aggregometry. RESULTS:Of 515 total patients included in both phases (mean age, 64.5 ± 11.4 years; 351 men [68.2%]; 450 with ACS [87.4%]), 52% were found to be clopidogrel responders based on results of platelet function testing. Among 135 patients in the prospective phase, there was a significantly lower proportion of patients who were clopidogrel responders in the Manufacturer 1 group compared with the Manufacturer 2 group (34.8% vs 55.1%, respectively; P=.03). After adjustment for age, sex, body mass index, aspirin response, therapeutic hypothermia, left heart catheterization indication, clopidogrel loading dose, time between loading dose and lab measurement, and manufacturer, aspirin response (odds ratio 0.96; 95% confidence interval, 0.95-0.97; P<.001) and manufacturer (odds ratio, 2.45; 95% confidence interval, 1.18-5.22; P=.02) were associated with clopidogrel response. CONCLUSIONS:In a large public hospital, we observed that pharmacodynamic response to clopidogrel varied by drug manufacturer. Further investigation and/or regulation is needed to minimize inter-manufacturer variability.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Alport syndrome is an inherited disease characterized by progressive loss of kidney function. We aimed to evaluate the safety and efficacy of bardoxolone methyl in patients with Alport syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:=80). Primary efficacy end points were change from baseline in eGFR at weeks 48 and 100. Key secondary efficacy end points were change from baseline in eGFR at weeks 52 and 104, after an intended 4 weeks off treatment. Safety was assessed by monitoring for adverse events and change from baseline in vital signs, 12-lead electrocardiograms, laboratory measurements (including, but not limited to, aminotransferases, urinary albumin-creatinine ratio, magnesium, and B-type natriuretic peptide), and body weight. RESULTS:). Discontinuations from treatment were more frequent among patients randomized to bardoxolone methyl; most discontinuations were due to protocol-specified criteria being met for increases in serum transaminases. Serious adverse events were more frequent among patients randomized to placebo. Three patients in each group developed kidney failure. CONCLUSIONS:In adolescent and adult patients with Alport syndrome receiving standard of care, treatment with bardoxolone methyl resulted in preservation in eGFR relative to placebo after a 2-year study period; off-treatment results using all available data were not significantly different. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER/UNASSIGNED:A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome - CARDINAL (CARDINAL), NCT03019185.