Faculty Bibliography

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).

A polygenic risk score (PGS) is associated with obstructive coronary artery disease (CAD) independent of traditional risk factors. Coronary computed tomography angiography (CTA) can characterize coronary plaques, including features of highrisk CAD. However, it is unknown if a PGS is associated with obstructive CAD and high-risk CAD phenotypes in patients with symptoms suggestive of CAD.

BACKGROUND:The 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. OBJECTIVES/OBJECTIVE:The 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. METHODS:Self-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). RESULTS:Among 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. CONCLUSIONS:More 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).

Prediabetes affects at least 1 in 3 adults in the U.S. and 1 in 5 in Europe. Although guidelines advocate aggressive management of lipid parameters in diabetes, most guidelines do not address treatment of dyslipidemia in prediabetes despite the increased atherosclerotic cardiovascular disease (ASCVD) risk. Several criteria are used to diagnose prediabetes: impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and HbA1c of 5.7-6.4%. Individuals with prediabetes have a greater risk of diabetes, a higher prevalence of dyslipidemia with a more atherogenic lipid profile and an increased risk of ASCVD. In addition to calculating ASCVD risk using traditional methods, an OGTT may further stratify risk. Those with 1-hour plasma glucose ≥8.6 mmol/L (155 mg/dL) and/or 2-hour ≥7.8 mmol/L (140 mg/dL) (IGT) have a greater risk of ASCVD. Diet and lifestyle modification are fundamental in prediabetes. Statins, ezetimibe and PCSK9 inhibitors are recommended in people requiring pharmacotherapy. Although high-intensity statins may increase risk of diabetes, this is acceptable because of the greater reduction of ASCVD. The LDL-C goal in prediabetes should be individualized. In those with IGT and/or elevated 1-hour plasma glucose, the same intensive approach to dyslipidemia as recommended for diabetes should be considered, particularly if other ASCVD risk factors are present.

Fine particulate matter air pollution (PM2.5) is a major contributor to cardiovascular morbidity and mortality, potentially via increased inflammation. PM2.5 exposure increases inflammatory biomarkers linked to cardiovascular disease, including CRP, IL-6 and TNFα. Portable air cleaners (PACs) reduce individual PM2.5 exposure but evidence is limited regarding whether PACs also reduce inflammatory biomarkers. We performed a systematic review and meta-analysis of trials evaluating the use of PACs to reduce PM2.5 exposure and inflammatory biomarker concentrations. We identified English-language articles of randomized sham-controlled trials evaluating high efficiency particulate air filters in non-smoking, residential settings measuring serum CRP, IL-6 and TNFα before and after active versus sham filtration, and performed meta-analysis on the extracted modeled percent change in biomarker concentration across studies. Of 487 articles identified, we analyzed 14 studies enrolling 778 participants that met inclusion criteria. These studies showed PACs reduced PM2.5 by 61.5 % on average. Of the 14 included studies, 10 reported CRP concentrations in 570 participants; these showed active PAC use was associated with 7 % lower CRP (95 % CI: −14 % to 0.0 %, p = 0.05). Nine studies of IL-6, with 379 participants, showed active PAC use was associated with 13 % lower IL-6 (95 % CI: [−23 %, −3 %], p = 0.009). Six studies, with 269 participants, reported TNF-α and demonstrated no statistical evidence of difference between active and sham PAC use. Portable air cleaners that reduce PM2.5 exposure can decrease concentrations of inflammatory biomarkers associated with cardiovascular disease. Additional studies are needed to evaluate clinical outcomes and other biomarkers.

The Trial to Assess Chelation Therapy 2 (TACT2) is an NIH-sponsored, randomized, 2x2 factorial, double masked, placebo-controlled, multicenter clinical trial testing 40 weekly infusions of a multi-component edetate disodium (disodium ethylenediamine tetra-acetic acid, or Na₂EDTA)-based chelation solution and twice daily oral, high-dose multivitamin and mineral supplements in patients with diabetes and a prior myocardial infarction (MI). TACT2 completed enrollment of 1000 subjects in December 2020, and infusions in December 2021. Subjects are being followed for 2.5 to 5 years. The primary endpoint is a composite of the time to first occurrence of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The trial is designed to have >85% power to detect a 30% relative reduction in the primary endpoint for each active treatment versus placebo comparison. TACT2 also includes a Trace Metals and Biorepository Core Lab, which will test the novel hypothesis that the prognostic benefits of chelation, if present, are due to removal of lead and cadmium from patients. Most of the design features of TACT2 were chosen to replicate selected features of the first TACT trial, which demonstrated a statistically significant reduction in cardiovascular outcomes in the EDTA chelation arm compared with placebo among patients with a prior MI, with the largest effect in patients with diabetes. Results from TACT2, if concordant with TACT, will provide definitive evidence of the benefit of edetate disodium-based chelation on cardiovascular outcomes, as well as the possible clinical importance of longitudinal changes in toxic metal levels of participants.