Tailoring Risk Prediction Models to Local Populations.

Importance: Risk estimation is an integral part of cardiovascular care. Local recalibration of guideline-recommended models could address the limitations of existing tools.

Objective: To provide a machine learning (ML) approach to augment the performance of the American Heart Association's Predicting Risk of Cardiovascular Disease Events (AHA-PREVENT) equations when applied to a local population while preserving clinical interpretability.

Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

Background: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels.

Methods: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.

Differences in Metabolomic Profiles Between Black and White Women and Risk of Coronary Heart Disease: an Observational Study of Women From Four US Cohorts.

Background: Racial differences in metabolomic profiles may reflect underlying differences in social determinants of health by self-reported race and may be related to racial disparities in coronary heart disease (CHD) among women in the United States. However, the magnitude of differences in metabolomic profiles between Black and White women in the United States has not been well-described. It also remains unknown whether such differences are related to differences in CHD risk.

Population median imputation was noninferior to complex approaches for imputing missing values in cardiovascular prediction models in clinical practice.

Objectives: To compare the validity and robustness of five methods for handling missing characteristics when using cardiovascular disease risk prediction models for individual patients in a real-world clinical setting.

Study Design And Setting: The performance of the missing data methods was assessed using data from the Swedish National Diabetes Registry (n = 419,533) with external validation using the Scottish Care Information - diabetes database (n = 226,953). Five methods for handling missing data were compared.

Adverse effects related to methotrexate polyglutamate levels: adjudicated results from the cardiovascular inflammation reduction trial.

Objectives: Methotrexate is widely used at low dosages (LD-MTX) for non-oncologic indications and is associated with a variety of adverse effects (AEs). We sought to determine whether concentrations of the active metabolite, MTX polyglutamates (MTX-PGs) 1-5, correlate with AEs.

Method: We examined data from the LD-MTX arm of the randomized double-blind Cardiovascular Inflammation Reduction Trial (CIRT).

Adverse Effects of Low-Dose Methotrexate in a Randomized Double-Blind Placebo-Controlled Trial: Adjudicated Hematologic and Skin Cancer Outcomes in the Cardiovascular Inflammation Reduction Trial.

Objective: Low-dose methotrexate (LD-MTX), a cornerstone in the treatment of rheumatoid arthritis, is associated with a moderately increased risk of anemia, leukopenia, and skin cancers, but the risks of myelosuppression and malignancy during LD-MTX use remain incompletely described. We examined the risks of cytopenias and skin cancers among patients taking LD-MTX versus placebo in a large randomized controlled trial (RCT).

Methods: We prespecified secondary analyses of a double-blind, placebo-controlled RCT that included adults with known cardiovascular disease and diabetes or metabolic syndrome in the United States and Canada.

Metabolomic Effects of Hormone Therapy and Associations With Coronary Heart Disease Among Postmenopausal Women.

Background: In the WHI-HT trials (Women's Health Initiative Hormone Therapy), treatment with oral conjugated equine estrogens and medroxyprogesterone acetate (CEE+MPA) resulted in increased risk of coronary heart disease (CHD), whereas oral conjugated equine estrogens (CEE) did not.

Methods: Four hundred eighty-one metabolites were measured at baseline and at 1-year in 503 and 431 participants in the WHI CEE and CEE+MPA trials, respectively. The effects of randomized HT on the metabolite profiles at 1-year was evaluated in linear models adjusting for baseline metabolite levels, age, body mass index, race, incident CHD, prevalent hypertension, and diabetes.

Pulmonary Adverse Events in Patients Receiving Low-Dose Methotrexate in the Randomized, Double-Blind, Placebo-Controlled Cardiovascular Inflammation Reduction Trial.

Objective: We previously reported that low-dose methotrexate (MTX) was associated with an increased risk of pulmonary adverse events (AEs) in a large randomized, placebo-controlled trial. Herein, we report details on the predictors and severity of pulmonary AEs.

Methods: We conducted a prespecified analysis of pulmonary AEs in the Cardiovascular Inflammation Reduction Trial.

Metabolic signatures associated with Western and Prudent dietary patterns in women.

Background: The Western dietary pattern (WD) is positively associated with risk of coronary artery disease (CAD) and cancer, whereas the Prudent dietary pattern (PD) may be protective. Foods may influence metabolite concentrations as well as oxidative stress and lipid dysregulation, biological mechanisms associated with CAD and cancer.

Objective: The aim was to assess the association of 2 derived dietary pattern scores with serum metabolites and identify metabolic pathways associated with the metabolites.

External Validation of a Risk Score for Major Toxicity Among Nonsteroidal Anti-Inflammatory Drug Users: Real-World Application.

Objective: We previously derived and validated a risk score for major nonsteroidal anti-inflammatory drug (NSAID) toxicity over 1 year among NSAID users in a randomized controlled trial. This work was extended to examine the risk score's performance in an external population using real-world data.

Methods: Patients enrolled in the Corrona Rheumatoid Arthritis (RA) Registry were included if they initiated use of an NSAID.

Adverse Effects of Low-Dose Methotrexate: A Randomized Trial.

Background: Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for more than 30 years, few data on adverse event (AE) rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred.

Objective: To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo.

Metabolomic profiles associated with all-cause mortality in the Women's Health Initiative.

Background: Metabolomics profiling has shown promise in elucidating the biological pathways underpinning mortality, but there are limited data in female populations.

Methods: We applied a liquid chromatography-tandem mass spectrometry metabolomics platform to EDTA-plasma to measure 470 metabolites at baseline in a discovery set of 943 postmenopausal women (including 417 incident deaths, median time to death of 10.6 years) with validation in an independent set of 1355 postmenopausal women (including 685 deaths, median time to death of 9.

Derivation and Validation of a Major Toxicity Risk Score Among Nonsteroidal Antiinflammatory Drug Users Based on Data From a Randomized Controlled Trial.

Objective: While nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used in rheumatology, they can cause major toxicity. Improving the risk/benefit ratio requires a more precise understanding of risk. This study was undertaken to derive and validate a risk score for major toxicity among NSAID users enrolled in a randomized controlled trial.

Estimating the receiver operating characteristic curve in matched case control studies.

The matched case-control design is frequently used in the study of complex disorders and can result in significant gains in efficiency, especially in the context of measuring biomarkers; however, risk prediction in this setting is not straightforward. We propose an inverse-probability weighting approach to estimate the predictive ability associated with a set of covariates. In particular, we propose an algorithm for estimating the summary index, area under the curve corresponding to the Receiver Operating Characteristic curve associated with a set of pre-defined covariates for predicting a binary outcome.

Low-Dose Methotrexate for the Prevention of Atherosclerotic Events.

Background: Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit.

Comparison of Cardiovascular Risk Factors for Coronary Heart Disease and Stroke Type in Women.

Background Cardiovascular risk factors have differential effects on various manifestations of cardiovascular disease, but to date direct formal comparisons are scarce, have been conducted primarily in men, and include only traditional risk factors. Methods and Results Using data from the multi-ethnic Women's Health Initiative Observational Study, we used a case-cohort design to compare 1731 women with incident cardiovascular disease during follow-up to a cohort of 1914 women. The direction of effect of all 24 risk factors (including various apolipoproteins, hemoglobin A1, high-sensitivity C-reactive protein, N-terminal pro-brain natriuretic peptide, and tissue plasminogen activator antigen) was concordant for coronary heart disease (CHD, defined as myocardial infarction and CHD death) and ischemic stroke; however, associations were generally stronger with CHD.

Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study.

Observational, genetic, and experimental data indicate that triglyceride rich lipoproteins (TRLs) likely participate causally in atherothrombosis. Yet, robust clinical trial evidence that triglyceride (TG) lowering therapy reduces cardiovascular events remains elusive. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARM-α), pemafibrate, will be used to target residual cardiovascular risk remaining after treatment to reduce low-density lipoprotein cholesterol (LDL-C) in individuals with the dyslipidemia of type 2 diabetes mellitus (T2).

Evaluation of the Pooled Cohort Risk Equations for Cardiovascular Risk Prediction in a Multiethnic Cohort From the Women's Health Initiative.

Importance: Atherosclerotic cardiovascular disease (ASCVD) kills approximately 1 in every 3 US women. Current cholesterol, hypertension, and aspirin guidelines recommend calculating 10-year risk of ASCVD using the 2013 Pooled Cohort Equations (PCE). However, numerous studies have reported apparent overestimation of risk with the PCE, and reasons for overestimation are unclear.

Metabolic Predictors of Incident Coronary Heart Disease in Women.

Background: Although metabolomic profiling offers promise for the prediction of coronary heart disease (CHD), and metabolic risk factors are more strongly associated with CHD in women than men, limited data are available for women.

Methods: We applied a liquid chromatography-tandem mass spectrometry metabolomics platform to measure 371 metabolites in a discovery set of postmenopausal women (472 incident CHD cases, 472 controls) with validation in an independent set of postmenopausal women (312 incident CHD cases, 315 controls).

Results: Eight metabolites, primarily oxidized lipids, were significantly dysregulated in cases after the adjustment for matching and CHD risk factors in both the discovery and validation data sets.

Reclassification calibration test for censored survival data: performance and comparison to goodness-of-fit criteria.

Background: The risk reclassification table assesses clinical performance of a biomarker in terms of movements across relevant risk categories. The Reclassification-Calibration (RC) statistic has been developed for binary outcomes, but its performance for survival data with moderate to high censoring rates has not been evaluated.

Methods: We develop an RC statistic for survival data with higher censoring rates using the Greenwood-Nam-D'Agostino approach (RC-GND).

Clinical risk reclassification at 10 years.

Three papers in this issue focus on the role of calibration in model fit statistics, including the net reclassification improvement (NRI) and integrated discrimination improvement (IDI). This commentary reviews the development of such reclassification statistics along with more recent advances in our understanding of these measures. We show how the two-category NRI and the IDI are affected by changes in the event rate in theory and in an applied example.