Pitavastatin to Prevent Cardiovascular Disease in HIV Infection.

BACKGROUND: The risk of cardiovascular disease is increased among persons with human immunodeficiency virus (HIV) infection, so data regarding primary prevention strategies in this population are needed. METHODS: In this phase 3 trial, we randomly assigned 7769 participants with HIV infection with a low-to-moderate risk of cardiovascular disease who were receiving antiretroviral therapy to receive daily pitavastatin calcium (at a dose of 4 mg) or placebo. The primary outcome was the occurrence of a major adverse cardiovascular event, which was defined as a composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral arterial ischemia, revascularization, or death from an undetermined cause. RESULTS: The median age of the participants was 50 years (interquartile range, 45 to 55); the median CD4 count was 621 cells per cubic millimeter (interquartile range, 448 to 827), and the HIV RNA value was below quantification in 5250 of 5997 participants (87.5%) with available data. The trial was stopped early for efficacy after a median follow-up of 5.1 years (interquartile range, 4.3 to 5.9). The incidence of a major adverse cardiovascular event was 4.81 per 1000 person-years in the pitavastatin group and 7.32 per 1000 person-years in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.48 to 0.90; P = 0.002). Muscle-related symptoms occurred in 91 participants (2.3%) in the pitavastatin group and in 53 (1.4%) in the placebo group; diabetes mellitus occurred in 206 participants (5.3%) and in 155 (4.0%), respectively. CONCLUSIONS: Participants with HIV infection who received pitavastatin had a lower risk of a major adverse cardiovascular event than those who received placebo over a median follow-up of 5.1 years. (Funded by the National Institutes of Health and others; REPRIEVE ClinicalTrials.gov number, NCT02344290.).

Design and Rationale of the Social Determinants of the Risk of Hypertension in Women of Reproductive Age (SAFE HEART) Study: An American Heart Association Research Goes Red Initiative.

BACKGROUND: Cardiovascular health literacy (CVHL) and social determinants of health (SDoH) play interconnected and critical roles in shaping cardiovascular health (CVH) outcomes. However, awareness of CVH risk has declined markedly, from 65% of women being aware that cardiovascular disease (CVD) is the leading cause of death for women in 2009 to just 44% being aware in 2019. The American Heart Association Research Goes Red (RGR) initiative seeks to develop an open-source, longitudinal, dynamic registry that will help women to be aware of and participate in research studies, and to learn about CVD prevention. We proposed to leverage this platform, particularly among Black and Hispanic women of reproductive age, to address CVHL gaps and advance health equity. METHODS: The primary objective of the study is to evaluate the cross-sectional association of cardiovascular health literacy (CVHL), SDoH using a polysocial score, and CVH in women of reproductive age at increased risk of developing hypertension (HTN). To achieve this we will use a cross-sectional study design, that engages women already enrolled in the RGR registry (registry-enrolled). To enhance the racial and ethnic/social economic diversity of the cohort, we will additionally enroll 300 women from the Baltimore and Washington D.C. community into the Social Determinants of the Risk of Hypertension in Women of Reproductive Age (SAFE HEART) Study. Community-enrolled and registry-enrolled women will undergo baseline social phenotyping including detailed SDoH questionnaire, CVH metrics assessment, and CVHL assessment. The secondary objective is to assess whether a 4-month active health education intervention will result in a change in CVHL in the 300 community-enrolled women. DISCUSSION: The SAFE HEART study examines the association between CVHL, SDoH, and CVH, with a focus on racial and ethnic minority groups and socioeconomically disadvantaged women of reproductive age, and the ability to improve these parameters by an educational intervention. These findings will inform the future development of community-engaged strategies that address CVHL and SDoH among women of reproductive age.

Real-world walking behaviors are associated with early-stage heart failure: a Project Baseline Health Study.

BACKGROUND: Data collected via wearables may complement in-clinic assessments to monitor subclinical heart failure (HF). OBJECTIVES: Evaluate the association of sensor-based digital walking measures with HF stage and characterize their correlation with in-clinic measures of physical performance, cardiac function and participant reported outcomes (PROs) in individuals with early HF. METHODS: The analyzable cohort included participants from the Project Baseline Health Study (PBHS) with HF stage 0, A, or B, or adaptive remodeling phenotype (without risk factors but with mild echocardiographic change, termed RF-/ECHO+) (based on available first-visit in-clinic test and echocardiogram results) and with sufficient sensor data. We computed daily values per participant for 18 digital walking measures, comparing HF subgroups vs stage 0 using multinomial logistic regression and characterizing associations with in-clinic measures and PROs with Spearman's correlation coefficients, adjusting all analyses for confounders. RESULTS: In the analyzable cohort (N=1265; 50.6% of the PBHS cohort), one standard deviation decreases in 17/18 walking measures were associated with greater likelihood for stage-B HF (multivariable-adjusted odds ratios [ORs] vs stage 0 ranging from 1.18-2.10), or A (ORs vs stage 0, 1.07-1.45), and lower likelihood for RF-/ECHO+ (ORs vs stage 0, 0.80-0.93). Peak 30-minute pace demonstrated the strongest associations with stage B (OR vs stage 0=2.10; 95% CI:1.74-2.53) and A (OR vs stage 0=1.43; 95% CI:1.23-1.66). Decreases in 13/18 measures were associated with greater likelihood for stage-B HF vs stage A. Strength of correlation with physical performance tests, echocardiographic cardiac-remodeling and dysfunction indices and PROs was greatest in stage B, then A, and lowest for 0. CONCLUSIONS: Digital measures of walking captured by wearable sensors could complement clinic-based testing to identify and monitor pre-symptomatic HF.

Diagnostic Strategies for the Assessment of Suspected Stable Coronary Artery Disease : A Systematic Review and Meta-analysis.

BACKGROUND: There is uncertainty about which diagnostic strategy for detecting coronary artery disease (CAD) provides better outcomes. PURPOSE: To compare the effect on clinical management and subsequent health effects of alternative diagnostic strategies for the initial assessment of suspected stable CAD. DATA SOURCES: PubMed, Embase, and Cochrane Central Register of Controlled Trials. STUDY SELECTION: Randomized clinical trials comparing diagnostic strategies for CAD detection among patients with symptoms suggestive of stable CAD. DATA EXTRACTION: Three investigators independently extracted study data. DATA SYNTHESIS: The strongest available evidence was for 3 of the 6 comparisons: coronary computed tomography angiography (CCTA) versus invasive coronary angiography (ICA) (4 trials), CCTA versus exercise electrocardiography (ECG) (2 trials), and CCTA versus stress single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) (5 trials). Compared with direct ICA referral, CCTA was associated with no difference in cardiovascular death and myocardial infarction (relative risk [RR], 0.84 [95% CI, 0.52 to 1.35]; low certainty) but less index ICA (RR, 0.23 [CI, 0.22 to 0.25]; high certainty) and index revascularization (RR, 0.71 [CI, 0.63 to 0.80]; moderate certainty). Moreover, CCTA was associated with a reduction in cardiovascular death and myocardial infarction compared with exercise ECG (RR, 0.66 [CI, 0.44 to 0.99]; moderate certainty) and SPECT-MPI (RR, 0.64 [CI, 0.45 to 0.90]; high certainty). However, CCTA was associated with more index revascularization (RR, 1.78 [CI, 1.33 to 2.38]; moderate certainty) but less downstream testing (RR, 0.56 [CI, 0.45 to 0.71]; very low certainty) than exercise ECG. Low-certainty evidence compared SPECT-MPI versus exercise ECG (2 trials), SPECT-MPI versus stress cardiovascular magnetic resonance imaging (1 trial), and stress echocardiography versus exercise ECG (1 trial). LIMITATION: Most comparisons primarily rely on a single study, many studies were underpowered to detect potential differences in direct health outcomes, and individual patient data were lacking. CONCLUSION: For the initial assessment of patients with suspected stable CAD, CCTA was associated with similar health effects to direct ICA referral, and with a health benefit compared with exercise ECG and SPECT-MPI. Further research is needed to better assess the relative performance of each diagnostic strategy. PRIMARY FUNDING SOURCE: None. (PROSPERO: CRD42022329635).

Changes in Body Mass Index with Longer-term Integrase Inhibitor Use: A Longitudinal Analysis of Data from the Randomized Trial to Prevent Vascular Events in Human Immunodeficiency Virus (REPRIEVE).

Over 2-years of follow-up, integrase strand transfer inhibitor (INSTI)-use was associated with weight gain among those on an INSTI <2 years at entry (+0.27 kg/m2/year; 95% confidence interval [CI], .22 to .33 vs +0.17 kg/m2/year; 95% CI, .12 to .23; P = .01), but not those on an entry INSTI >2 years.

Pericoronary Adipose Tissue Density, Inflammation, and Subclinical Coronary Artery Disease Among People With HIV in the REPRIEVE Cohort.

BACKGROUND: Pericoronary adipose tissue (PCAT) may influence plaque development through inflammatory mechanisms. We assessed PCAT density, as a measure of pericoronary inflammation, in relationship to coronary plaque among people with human immunodeficiency virus (HIV [PWH]) and to a matched control population. METHODS: In this baseline analysis of 727 participants of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) Mechanistic Substudy, we related computed tomography-derived PCAT density to presence and extent (Leaman score) of coronary artery disease (CAD), noncalcified plaque, coronary artery calcium (CAC), and vulnerable plaque features using multivariable logistic regression analyses. We further compared the PCAT density between PWH and age, sex, body mass index, CAC score, and statin use-matched controls from the community-based Framingham Heart Study (N = 464), adjusting for relevant clinical covariates. RESULTS: Among 727 REPRIEVE participants (age 50.8 ± 5.8 years; 83.6% [608/727] male), PCAT density was higher in those with (vs without) coronary plaque, noncalcified plaque, CAC >0, vulnerable plaque, and high CAD burden (Leaman score >5) (P < .001 for each comparison). PCAT density related to prevalent coronary plaque (adjusted odds ratio [per 10 HU]: 1.44; 95% confidence interval, 1.22-1.70; P < .001), adjusted for clinical cardiovascular risk factors, body mass index, and systemic immune/inflammatory biomarkers. Similarly, PCAT density related to CAC >0, noncalcified plaque, vulnerable plaque, and Leaman score >5 (all P ≤ .002). PCAT density was greater among REPRIEVE participants versus Framingham Heart Study (-88.2 ± 0.5 HU versus -90.6 ± 0.4 HU; P < .001). CONCLUSIONS: Among PWH in REPRIEVE, a large primary cardiovascular disease prevention cohort, increased PCAT density independently associated with prevalence and severity of coronary plaque, linking increased coronary inflammation to CAD in PWH.

Sex Differences in Subclinical Atherosclerosis and Systemic Immune Activation/Inflammation Among People With Human Immunodeficiency Virus in the United States.

BACKGROUND: Among people with HIV (PWH), sex differences in presentations of atherosclerotic cardiovascular disease (ASCVD) may be influenced by differences in coronary plaque parameters, immune/inflammatory biomarkers, or relationships therein. METHODS: REPRIEVE, a primary ASCVD prevention trial, enrolled antiretroviral therapy (ART)-treated PWH. At entry, a subset of US participants underwent coronary computed tomography angiography (CTA) and immune phenotyping (n = 755 CTA; n = 725 CTA + immune). We characterized sex differences in coronary plaque and immune/inflammatory biomarkers and compared immune-plaque relationships by sex. Unless noted otherwise, analyses adjust for ASCVD risk score. RESULTS: The primary analysis cohort included 631 males and 124 females. ASCVD risk was higher among males (median: 4.9% vs 2.1%), while obesity rates were higher among females (48% vs 21%). Prevalence of any plaque and of plaque with either ≥1 visible noncalcified portion or vulnerable features (NC/V-P) was lower among females overall and controlling for relevant risk factors (RR [95% CI] for any plaque: .67 [.50, .92]; RR for NC/V-P: .71 [.51, 1.00] [adjusted for ASCVD risk score and body mass index]). Females showed higher levels of IL-6, hs-CRP, and D-dimer and lower levels of Lp-PLA2 (P < .001 for all). Higher levels of Lp-PLA2, MCP-1, and oxLDL were associated with higher plaque (P < .02) and NC/V-P prevalence, with no differences by sex. Among females but not males, D-dimer was associated with higher prevalence of NC/V-P (interaction P = .055). CONCLUSIONS: Among US PWH, females had a lower prevalence of plaque and NC/V-P, as well as differences in key immune/inflammatory biomarkers. Immune-plaque relationships differed by sex for D-dimer but not other tested parameters. Clinical Trial Registration. ClinicalTrials.gov; identifier: NCT0234429 (date of initial registration: 22 January 2015).

Cytomegalovirus Immunoglobulin G (IgG) Titer and Coronary Artery Disease in People With Human Immunodeficiency Virus (HIV).

BACKGROUND: Cytomegalovirus (CMV) infection is thought to result in increased immune activation in people with human immunodeficiency virus (HIV, PWH). Although some data have linked asymptomatic CMV infection to cardiovascular disease among PWH, it remains unknown whether CMV is associated with increased or high-risk coronary plaque. METHODS: The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) enrolled PWH aged 40-75 years on stable antiretroviral therapy (ART) with low-to-moderate atherosclerotic cardiovascular disease (ASCVD) risk. Among a subset of US REPRIEVE participants, coronary plaque was assessed by coronary computed tomography angiography. Here, we assessed the relationship between CMV immunoglobulin G (IgG) titer and (1) levels of immune activation, (2) inflammatory biomarkers, and (3) coronary plaque phenotypes at study entry. RESULTS: Of 672 participants, mean age was 51 years, 83% were men, median ASCVD risk score was 4.5%, and 66% had current CD4+ T-cell count ≥500 cells/mm3. Higher CMV IgG quartile group was associated with older age and lower current and nadir CD4+ T-cell counts. CMV IgG titer was associated with specific inflammatory biomarkers (sCD163, MCP-1, interleukin [IL]-6, hsCRP) in univariate analysis, but not after controlling for HIV-specific factors. In contrast, CMV IgG titer was not associated with coronary artery disease indexes, including presence of plaque, coronary artery calcium (CAC) score >0, vulnerable plaque presence, or Leaman score >5. CONCLUSIONS: No meaningful association was seen between CMV IgG titer and coronary artery disease indexes among ART-treated PWH at study enrollment. Longitudinal assessments in REPRIEVE will determine the relationship of CMV IgG titer to plaque progression and cardiovascular events. CLINICAL TRIALS REGISTRATION: NCT02344290.

Variation in resource utilization and mortality among patients with varying MR type and severity.

BACKGROUND: Limited data exists regarding the relationships between resource use and outcomes in patients with mitral regurgitation (MR). We examined resource utilization and outcomes across MR type and severity. METHODS: Using the Duke Echocardiography Laboratory Database, we identified patients with an index echo demonstrating moderate or severe MR (2000-2016) and examined 5-year cumulative rates of resources (ie, TTE, TEE, cardiac catheterization, cardiology/CTS referral, MV surgery/TEER, hospitalizations) by severity and type. We performed a multivariable landmark analysis of resource use during a 6 to 12 month period and 5-year mortality; and a multivariable analysis of the association between MR type and 5-year hospitalization costs. RESULTS: Among 4,511 patients with moderate or severe MR, 84.7% had moderate MR and 42.2% had secondary ischemic MR. The median age was 70 years-moderate, 66 years-severe. The mean 5-year cumulative resource utilization rate was 11.1 encounters/patients. Among patients with moderate or severe MR, there was significant variation in utilization of each resource by MR type (all P < .05). For severe MR, the performance of cardiac catheterization or MV surgery during the landmark period was associated with significantly lower mortality; for moderate MR, CTS referral during the landmark was associated with significantly lower mortality (P < .05). Patients with secondary ischemic and non-ischemic MR had significantly higher 5-year hospitalization costs compared with primary myxomatous MR (P < .05). CONCLUSIONS: Resource utilization and outcomes vary by MR type and severity. Utilization of resources, such as TTE, during guideline-recommended surveillance periods was not associated with a reduction in mortality while other care (catheterization or surgery) was associated with improved survival.

Clinical and cost implications of deferred testing in low-risk patients with stable chest pain: a simulation using the PROMISE trial.

Current guidelines recommend a deferred testing approach in low-risk patients presenting with stable chest pain. After simulating a deferred testing approach using the PROMISE Minimal Risk Score to identify 915 minimal risk participants with cost data from the PROMISE trial, a deferred testing strategy was associated with an adjusted cost savings of -$748.74 (95% CI: -1646.97, 158.06) per participant and 74.6% of samples had better clinical outcomes and lower mean cost. This supports the current guideline recommended deferred testing approach in low-risk patients with stable chest pain.

Clinical and Echocardiographic Diversity Associated With Physical Fitness in the Project Baseline Health Study: Implications for Heart Failure Staging.

BACKGROUND: Clinical and echocardiographic features may carry diverse information about the development of heart failure (HF). Therefore, we determined heterogeneity in clinical and echocardiographic phenotypes and its association with exercise capacity. METHODS: In 2036 community-dwelling individuals, we defined echocardiographic profiles of left and right heart remodeling and dysfunction. We subdivided the cohort based on presence (+) or absence (-) of HF risk factors (RFs) and echocardiographic abnormalities (RF-/Echo-, RF-/Echo+, RF+/Echo-, RF+/Echo+). Multivariable-adjusted associations between subgroups and physical performance metrics from 6-minute walk and treadmill exercise testing were assessed. RESULTS: The prevalence was 35.3% for RF-/Echo-, 4.7% for RF-/Echo+, 39.3% for RF+/Echo-, and 20.6% for RF+/Echo+. We observed large diversity in echocardiographic profiles in the Echo+ group. Participants with RF-/Echo+ (18.6% of Echo+) had predominantly echocardiographic abnormalities other than left ventricular (LV) diastolic dysfunction, hypertrophy and reduced ejection fraction, whereas their physical performance was similar to RF-/Echo-. In contrast, participants with RF+/Echo+ presented primarily with LV hypertrophy or dysfunction, features that related to lower 6-minute walking distance and lower exercise capacity. CONCLUSIONS: Subclinical echocardiographic abnormalities suggest HF pathogenesis, but the presence of HF risk factors and type of echo abnormality should be considered so as to distinguish adverse from benign adaptation and to stratify HF risk.

Relationship between obesity severity, metabolic status and cardiovascular disease in obese adults.

BACKGROUND: Evidence about the associations between obesity severity, metabolic status and risk of incident cardiovascular disease (CVD) in adults with obesity remains limited. METHODS: The study included 109,301 adults with obesity free of prior CVD based on the UK Biobank cohort. Metabolic status was categorized into metabolically healthy obesity (MHO; free of hypertension, hypercholesterolemia and diabetes) and metabolically unhealthy obesity (MUO). Obesity severity was classified into three levels: class I (body mass index of 30.0-34.9 kg/m2 ), II (35.0-39.9) and III (≥40.0). Cox proportional hazards models were used for analyses. RESULTS: There were 8059 incident CVD events during a median follow-up of 8.1 years. MUO was significantly associated with a 74% increased CVD risk compared with MHO (HR = 1.74, 95% CI: 1.62-1.83). There was a significant interaction between obesity severity and metabolic status on an additive scale regarding CVD risk. When taking class I obesity as reference, class II was nonsignificantly associated with an increased risk of CVD in the MHO group (HR = 1.07, 95% CI: 0.90-1.27), while class III was significantly related to increased risks of CVD (HR = 1.48, 95% CI: 1.12-1.96). In the MUO group, both classes II and III were significantly related to increased risks of CVD. Significant subgroup effects of age (p = .009) and sex (p = .047) were observed among participants with MUO but not in the MHO group. CONCLUSIONS: Both elevated obesity severity and MUO were significantly associated with increased risks of CVD in adults with obesity, while metabolic status could modify the relationship between obesity severity and CVD risk. More research is needed to further clarify the relationship.

Prognostic value of CT-derived coronary artery disease characteristics varies by ASCVD risk: insights from the PROMISE trial.

OBJECTIVES: To compare the prognostic value of individual CT-derived coronary artery disease (CAD) characteristics across categories of clinical cardiovascular risk. METHODS: The central core laboratory assessed coronary artery calcium (CAC), obstructive CAD (stenosis ≥ 50%), and high-risk plaque (HRP) in stable outpatients with suspected CAD enrolled in the PROMISE trial. Multivariable Cox regression models (endpoint: unstable angina, nonfatal myocardial infarction, or all-cause mortality; median follow-up: 2 years) were used to compare hazard ratios (HR) of the CT measures between low-borderline (< 7.5%) and moderate-high (≥ 7.5%) atherosclerotic cardiovascular disease (ASCVD) risk based on the pooled cohort equation. RESULTS: Among 4356 included patients (aged 61 ± 8 years, 52% women), 67% had ASCVD risk ≥ 7.5%. Stratified by ASCVD risk, CAD ≥ 50% had nearly threefold greater HR in individuals with ASCVD < 7.5% (aHR, 6.85; 95% CI, 2.33-20.15; p < 0.001) vs. ASCVD ≥ 7.5% (aHR: 2.66, 95% CI: 1.67-4.25, p < 0.001; interaction p = 0.041). CAC predicted events solely in ASCVD ≥ 7.5% patients (aHR: 1.92, 95% CI: 1.01-3.63, p = 0.045; interaction p = 0.571), while HRP predicted events only in ASCVD < 7.5% (aHR: 3.11, 95% CI: 1.09-8.85, p = 0.034; interaction p = 0.034). CONCLUSIONS: Prognostic values of CT-derived CAD characteristics differ by ASCVD risk categories. While CAD ≥ 50% has the highest prognostic value regardless of ASCVD risk, CAC is prognostic in high and HRP in low ASCVD risk. These findings suggest that CAD ≥ 50% and HRP detection rather than CAC scoring may better risk-stratify symptomatic low-risk patients and thus potentially improve downstream care. KEY POINTS: • Prognostic value of individual CT-derived CAD characteristics differs by categories of cardiovascular risk. • Presence of obstructive coronary artery stenosis ≥ 50% has the highest prognostic value regardless of cardiovascular risk. • Coronary artery calcium is independently prognostic in high and high-risk plaque features in low cardiovascular risk.

Proteomic Signature of Subclinical Coronary Artery Disease in People With HIV: Analysis of the REPRIEVE Mechanistic Substudy.

BACKGROUND: People with HIV (PWH) have subclinical coronary artery disease (CAD) despite low traditional atherosclerotic cardiovascular disease (ASCVD) risk scores. Coronary plaque in PWH presents as a unique phenotype, but little is known about the contributions of specific inflammatory pathways to plaque phenotypes in PWH. METHODS: The REPRIEVE Mechanistic Substudy enrolled PWH on ART without known cardiovascular disease. We used a targeted discovery proteomics approach to evaluate 246 unique proteins representing cardiovascular, inflammatory, and immune pathways. Proteomic signatures were determined for presence of coronary artery calcium (CAC > 0) and presence of coronary plaque. RESULTS: Data were available for 662 participants (aged 51 [SD 6] years, ASCVD risk score 4.9% [SD 3.1%]). Among 12 proteins associated with both CAC and presence of coronary plaque, independent of ASCVD risk score, the odds ratios were highest for NRP1: 5.1 (95% confidence interval [CI], 2.3-11.4) for CAC and 2.9 (95% CI, 1.4-6.1) for presence of plaque. Proteins uniquely related to presence of plaque were CST3, LTBR, MEPE, PLC, SERPINA5, and TNFSF13B; in contrast, DCN, IL-6RA, OSMR, ST2, and VCAM1 were only related to CAC. CONCLUSIONS: Distinct immune and inflammatory pathways are differentially associated with subclinical CAD phenotypes among PWH. This comprehensive set of targets should be further investigated to reduce atherosclerosis and ASCVD in PWH. CLINICAL TRIALS REGISTRATION: NCT02344290.

COVID-19 Vaccination Rates in a Global HIV Cohort.

Little is known regarding coronavirus disease 2019 (COVID-19) vaccination rates in people with HIV (PWH), a vulnerable population with significant morbidity from COVID-19. We assessed COVID-19 vaccination rates among 6952 PWH in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) compared to region- and country-specific vaccination data. The global probability of COVID-19 vaccination through end of July 2021 was 55% among REPRIEVE participants with rates varying substantially by Global Burden of Disease (GBD) superregion. Among PWH, factors associated with COVID-19 vaccination included residence in high-income regions, age, white race, male sex, body mass index, and higher cardiovascular risk. Clinical Trials Registration. NCT02344290.

Exploring ethnic representativeness in diabetes clinical trial enrolment from 2000 to 2020: a chronological survey.

AIMS/HYPOTHESIS: Ethnic representativeness of participant enrolment in diabetes RCTs involving multiple ethnicities remains unknown. The aims of this study were to evaluate the status and temporal trend of ethnic representativeness in enrolment to diabetes RCTs, and to assess under-enrolment of non-white ethnic groups and explore trial characteristics associated with under-enrolment. METHODS: We conducted a chronological survey by systematically searching the literature to include eligible RCTs published between January 2000 and December 2020. We assessed temporal trends in enrolment of ethnic groups in the included trials. Univariable logistic regression was used to explore the association between trial characteristics and under-enrolment of non-white groups, using a participant to prevalence ratio of <0.8 to define under-enrolment. This study was registered in PROSPERO (CRD42021229100). RESULTS: We included 405 RCTs for analysis (327 multi-country trials, 69 conducted in the USA and nine conducted in the UK). The median enrolment rate of all non-white groups was 24.0% in the overall RCTs. Trials conducted in the USA and the UK had median enrolment rates of 29.0% and 12.0% for all non-white groups, respectively. There was a temporal trend towards increased participation of non-white ethnic groups in the overall RCTs; however, no significant improvement over time was found in the US or UK trials. Non-white groups were under-enrolled in most included trials: 62.3% (43/69) in US trials and 77.8% (7/9) in UK trials. The US trials with a high female proportion were associated with lower odds of under-enrolment of all non-white groups (OR 0.22; 95% CI 0.07, 0.65), while trials receiving funding from industry showed increased odds of under-enrolment (OR 4.64; 95% CI 1.50, 14.35). Outpatient enrolment and intervention duration were significantly associated with under-enrolment of Black participants. Only a small proportion of trials reported subgroup results or explored the effect modification by ethnicity. CONCLUSIONS/INTERPRETATION: A temporal trend towards increased non-white ethnic enrolment was found in diabetes RCTs globally, but not in the USA or the UK. Non-white ethnic groups were under-represented in the majority of diabetes trials conducted in the USA and the UK. Some trial characteristics may be associated with non-white under-enrolment in diabetes trials. These findings provide some evidence for non-white ethnic representativeness in diabetes trials over the past two decades, and highlight the need for more effective strategies and endeavours to alleviate under-enrolment of non-white ethnic groups.

Geographical Differences in the Self-Reported Functional Impairment of People With Human Immunodeficiency Virus (HIV) and Associations With Cardiometabolic Risk.

BACKGROUND: We sought to explore multinational differences in functional status by global burden of disease (GBD) regions in the REPRIEVE cohort. METHODS: REPRIEVE is a prospective, double-blind, randomized, placebo-controlled, multicenter, phase III primary cardiovascular prevention study of pitavastatin calcium vs placebo among people with human immunodeficiency virus (HIV, PWH) ages 40-75 on antiretroviral therapy (ART). GBD super regions were defined using World Health Organization classifications. Participants were categorized by impairment on the Duke Activity Status Instrument (DASI: none, some, moderate, severe). Logistic regression models examined risk factors and GBD regions associated with functional impairment. The association between functional impairment and cardiometabolic risk was also explored. RESULTS: Of 7736 participants, the majority were from high-income countries (n = 4065), were male (65%), and had received ART for ≥ 10 years. The median DASI score was 58.2 (interquartile range [IQR] 50.2, 58.2); 36% reported at least some impairment. In adjusted analyses, functional impairment was significantly more frequent among participants from Southeast/East Asia. Other factors associated with greater impairment included female sex, Black race, older age, current/former smoking, higher body mass index, use of ART for ≥ 10 years, and select ART regimens; differences were seen in risks across GBD regions. Functional impairment was associated with increased cardiometabolic risk. CONCLUSIONS: Over 1/3 of middle-aged and older PWH in a global cohort across diverse GBD regions demonstrate functional impairments. The associations between DASI and cardiometabolic risk suggest that a measure of functional status may improve risk prediction; these longitudinal associations will be further investigated over REPRIEVE trial follow-up.

Factors Associated With Systemic Immune Activation Indices in a Global Primary Cardiovascular Disease Prevention Cohort of People With Human Immunodeficiency Virus on Antiretroviral Therapy.

BACKGROUND: Among antiretroviral therapy (ART)-treated people with human immunodeficiency virus (PWH), persistent systemic immune activation contributes to atherogenesis atherosclerotic, cardiovascular disease (CVD) events, and mortality. Factors associated with key immune activation indices have not previously been characterized among a global primary CVD prevention cohort of PWH. METHODS: Leveraging baseline Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) data, we evaluated factors associated with soluble CD14 (sCD14) and oxidized low-density lipoprotein (oxLDL). RESULTS: The primary analysis cohort included 4907 participants from 5 global-burden-of-disease regions (38% female, 48% Black, median age 50 years). In fully adjusted models for sCD14, female sex and White race (among those in high-income regions) were associated with higher sCD14 levels, while higher body mass index (BMI) and current use of nucleoside reverse transcriptase inhibitor + integrase strand transfer inhibitor ART were associated with lower sCD14 levels. In fully adjusted models for oxLDL, male sex, residence in high-income regions, White race (among those in high-income regions), and higher BMI were associated with higher oxLDL levels. In a subanalysis cohort of 1396 women with HIV, increased reproductive age was associated with higher sCD14 levels but not with higher oxLDL levels. CONCLUSIONS: Factors associated with sCD14 and oxLDL, 2 key indices of immune-mediated CVD risk, differ. Future studies will elucidate ways in which medications (eg, statins) and behavioral modifications influence sCD14 and oxLDL and the extent to which dampening of these markers mediates CVD-protective effects. CLINICAL TRIALS REGISTRATION: NCT0234429.

Associations of a polygenic risk score with coronary artery disease phenotypes in the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial.

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.