Staging and clean room: Constructs designed to facilitate transparency and reduce bias in comparative analyses of real-world data.

Purpose: We describe constructs designed to protect the integrity of the results from comparative analyses using real-world data (RWD): staging and clean room.

Methods: Staging involves performing sequential preliminary analyses and evaluating the population size available and potential bias before conducting comparative analyses. A clean room involves restricted access to data and preliminary results, policies governing exploratory analyses and protocol deviations, and audit trail.

Ancestral diversity in lipoprotein(a) studies helps address evidence gaps.

Introduction: The independent and causal cardiovascular disease risk factor lipoprotein(a) (Lp(a)) is elevated in >1.5 billion individuals worldwide, but studies have prioritised European populations.

Methods: Here, we examined how ancestrally diverse studies could clarify Lp(a)'s genetic architecture, inform efforts examining application of Lp(a) polygenic risk scores (PRS), enable causal inference and identify unexpected Lp(a) phenotypic effects using data from African (n=25 208), East Asian (n=2895), European (n=362 558), South Asian (n=8192) and Hispanic/Latino (n=8946) populations.

Retrospective comparison of traditional and artificial intelligence-based heart failure phenotyping in a US health system to enable real-world evidence.

Objective: Quantitatively evaluate the quality of data underlying real-world evidence (RWE) in heart failure (HF).

Design: Retrospective comparison of accuracy in identifying patients with HF and phenotypic information was made using traditional (ie, structured query language applied to structured electronic health record (EHR) data) and advanced (ie, artificial intelligence (AI) applied to unstructured EHR data) RWE approaches. The performance of each approach was measured by the harmonic mean of precision and recall (F score) using manual annotation of medical records as a reference standard.

Lipoprotein(a) and the Risk for Recurrent Atherosclerotic Cardiovascular Events Among Adults With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

Rationale & Objective: Many adults with chronic kidney disease (CKD) and atherosclerotic cardiovascular disease (ASCVD) have high lipoprotein(a) levels. It is unclear whether high lipoprotein(a) levels confer an increased risk for recurrent ASCVD events in this population. We estimated the risk for recurrent ASCVD events associated with lipoprotein(a) in adults with CKD and prevalent ASCVD.

Lipoprotein(a) and the Risk for Coronary Heart Disease and Ischemic Stroke Events Among Black and White Adults With Cardiovascular Disease.

Background It is unclear whether lipoprotein(a) is associated with coronary heart disease (CHD) and ischemic stroke events in White and Black adults with atherosclerotic cardiovascular disease (ASCVD). Methods and Results We conducted a case-cohort analysis, including Black and White REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants ≥45 years of age with prevalent ASCVD (ie, CHD or stroke) at baseline between 2003 and 2007. Baseline lipoprotein(a) molar concentration was measured in participants with ASCVD who experienced a CHD event by December 2017 (n=1166) or an ischemic stroke by September 2019 (n=492) and in a random subcohort of participants with prevalent ASCVD (n=1948).

Race/ethnic and sex differences in the initiation of non-statin lipid-lowering medication following myocardial infarction.

Background: Adults with atherosclerotic cardiovascular disease (ASCVD) at very high-risk for recurrent events who have low-density lipoprotein cholesterol ≥ 70 mg/dL despite maximally-tolerated statin therapy are recommended to initiate ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.

Objective: Compare the initiation of ezetimibe and a PCSK9 inhibitor after a myocardial infarction (MI) among very high-risk ASCVD patients by race/ethnicity and sex.

Methods: We analyzed data from 374,786 adults ≥ 66 years of age with Medicare fee-for-service coverage who had an MI between July 1, 2015 and December 31, 2018, were not taking ezetimibe or a PCSK9 inhibitor, and had very high-risk ASCVD defined by the 2018 American Heart Association/American College of Cardiology multi-society cholesterol guideline.

Death, long-term nursing home placement, and impoverishment after recurrent myocardial infarction.

Study Objective: To determine whether recurrent myocardial infarction (MI) is associated with increased risk of mortality, long-term nursing home placement, and impoverishment.

Design: Retrospective cohort study.

Setting: United States Medicare program.

Factors Associated With PCSK9 Inhibitor Initiation Among US Veterans.

Background Few adults at high risk for atherosclerotic cardiovascular disease events use a PCSK9i (proprotein convertase subtilisin/kexin type 9 inhibitor). Methods and Results Using data from the US Veterans Health Administration, we identified veterans who initiated a PCSK9i between January 2018 and December 2019, matched 1:4 to veterans who did not initiate this medication over this time period (case-cohort study). Two cohorts of veterans were analyzed: (1) atherosclerotic cardiovascular disease, with a most recent low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL; and (2) severe hypercholesterolemia (ie, familial hypercholesterolemia or any prior LDL-C ≥190 mg/dL, with most recent LDL-C ≥100 mg/dL).

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC).

Long-Term Levels of LDL-C and Cognitive Function: The CARDIA Study.

Objectives: It is uncertain if long-term levels of low-density lipoprotein-cholesterol (LDL-C) affect cognition in middle age. We examined the association of LDL-C levels over 25 years with cognitive function in a prospective cohort of black and white US adults.

Methods: Lipids were measured at baseline (1985-1986; age: 18-30 years) and at serial examinations conducted over 25 years.

Atherosclerotic Risk and Statin Use Among Patients With Peripheral Artery Disease.

Background: Peripheral artery disease (PAD) is associated with increased risk for atherosclerotic cardiovascular disease (ASCVD) events.

Objectives: The goal of this study was to compare the risk for ASCVD events and the use of statins among patients with PAD versus those with coronary heart disease (CHD) or cerebrovascular disease.

Methods: The authors conducted a retrospective cohort study of adults age ≥19 years with commercial or Medicare health insurance who had a history of PAD, CHD, or cerebrovascular disease on December 31, 2014.

Designing, Conducting, Monitoring, and Analyzing Data from Pragmatic Randomized Clinical Trials: Proceedings from a Multi-stakeholder Think Tank Meeting.

In late 2018, the Food and Drug Administration (FDA) outlined a framework for evaluating the possible use of real-world evidence (RWE) to support regulatory decision-making. This framework was created to facilitate studies that would generate high-quality RWE, including pragmatic clinical trials (PCTs), which are randomized trials designed to inform clinical or policy decisions by assessing the real-world effectiveness of an intervention. There is general agreement among experts that the use of existing healthcare and patient-generated data holds promise for making randomized trials more efficient, less costly, and more generalizable.

Use of Low-Density Lipoprotein-Lowering Therapies Before and After PCSK9 Inhibitor Initiation.

Background Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are used to reduce low-density lipoprotein (LDL) cholesterol. PCSK9i use after initiation, as well as persistence with or alterations to other LDL-lowering therapy after PCSK9i initiation, is not well understood. Methods and Results We conducted a retrospective study of alirocumab or evolocumab (PCSK9i) new users from July 2015 to December 2017 in the MarketScan Early View database of US commercial insurance beneficiaries.

Residual risk for coronary heart disease events and mortality despite intensive medical management after myocardial infarction.

Background: High-intensity statins, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and antiplatelet agents (ie, intensive medical management) reduce coronary heart disease (CHD) risk after myocardial infarction (MI).

Objective: The objective of the study was to determine the risk of CHD events or death despite receiving intensive medical management after MI.

Methods: We studied 16,853 United States adults with health insurance in the MarketScan and Medicare databases who underwent percutaneous coronary intervention while hospitalized for MI between January 1, 2014 and June 30, 2015 and received intensive medical management within 30 days after hospital discharge.

Excess Risk for Atherosclerotic Cardiovascular Outcomes Among US Adults With HIV in the Current Era.

Background In the 2000s, adults with HIV had a higher risk for atherosclerotic cardiovascular disease (ASCVD) compared with those without HIV. There is uncertainty if this excess risk still exists in the United States given changes in antiretroviral therapies and increased statin use. Methods and Results We compared the risk for ASCVD events between US adults aged ≥19 years with and without HIV who had commercial or supplemental Medicare health insurance between January 1, 2011, and December 31, 2016.

Trends in statin utilization among adults with severe peripheral artery disease including critical limb ischemia in an integrated healthcare delivery system.

Evidence suggests that statin therapy in patients with peripheral artery disease (PAD) is beneficial yet use remains suboptimal. We examined trends in statin use, intensity, and discontinuation among adults aged ⩾ 40 years with incident severe PAD and a subset with critical limb ischemia (CLI) between 2002 and 2015 within an integrated healthcare delivery system. Discontinuation of statin therapy was defined as the first 90-day gap in treatment within 1 year following PAD diagnosis.

PCSK9 loss-of-function variants and Lp(a) phenotypes among black US adults.

The pharmacologic inhibition of proprotein convertase subtilisin-kexin type 9 (PCSK9) lowers lipoprotein (a) [Lp(a)] concentrations. However, the impact of genetic PCSK9 loss-of-function variants (LOFVs) on Lp(a) is uncertain. We determined the association of PCSK9 LOFVs with Lp(a) measures among black adults.

Real world evidence in cardiovascular medicine: ensuring data validity in electronic health record-based studies.

Objective: With growing availability of digital health data and technology, health-related studies are increasingly augmented or implemented using real world data (RWD). Recent federal initiatives promote the use of RWD to make clinical assertions that influence regulatory decision-making. Our objective was to determine whether traditional real world evidence (RWE) techniques in cardiovascular medicine achieve accuracy sufficient for credible clinical assertions, also known as "regulatory-grade" RWE.

Lipid-Lowering Prescription Patterns in Patients With Diabetes Mellitus or Cardiovascular Disease.

The purpose of this study is to describe lipid-lowering therapy (LLT) prescriptions and low-density lipoprotein cholesterol (LDL-C) monitoring in patients with diabetes mellitus (DM) with or without concomitant cardiovascular disease (CVD). Olmsted County, Minnesota residents with a first-ever diagnosis of DM or CVD (ischemic stroke/transient ischemic attack, myocardial infarction, unstable angina pectoris, or revascularization procedure) between 2005 and 2012 were classified as having DM only, CVD only, or CVD + DM. All LLT prescriptions and LDL-C measurements were obtained for 2 years after diagnosis.

Association of Region and Hospital and Patient Characteristics With Use of High-Intensity Statins After Myocardial Infarction Among Medicare Beneficiaries.

Importance: High-intensity statin use after myocardial infarction (MI) varies by patient characteristics, but little is known about differences in use by hospital or region.

Objective: To explore the relative strength of associations of region and hospital and patient characteristics with high-intensity statin use after MI.

Design, Setting, And Participants: This retrospective cohort analysis used Medicare administrative claims and enrollment data to evaluate fee-for-service Medicare beneficiaries 66 years or older who were hospitalized for MI from January 1, 2011, through June 30, 2015, with a statin prescription claim within 30 days of discharge.

Familial Hypercholesterolemia Among Young Adults With Myocardial Infarction.

Background: There are limited data on the prevalence and treatment of familial hypercholesterolemia (FH) among U.S. adults who experience a myocardial infarction (MI) at a young age.

Characteristics and Cardiovascular Disease Event Rates among African Americans and Whites Who Meet the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) Trial Inclusion Criteria.

Purpose: Determine the risk for cardiovascular disease (CVD) events among adults with clinically evident CVD who meet the inclusion criteria for the FOURIER clinical trial on PCSK9 inhibition in a real-world database.

Methods: We analyzed data from 2072 African American and 2972 white REasons for Geographic And Racial Differences in Stroke (REGARDS) study participants 45-85 years of age with clinically evident CVD. Study participants meeting the FOURIER inclusion criteria (one major or two minor cardiovascular risk factors, fasting LDL cholesterol ≥ 70 mg/dL or non-HDL cholesterol ≥ 100 mg/dL, triglycerides ≤ 400 mg/dL, and taking statin) were followed for CVD events (myocardial infarction, stroke, coronary revascularization, and CVD death) from baseline in 2003-2007 through 2014.

Excess Deaths Attributable to Influenza-Like Illness in the ESRD Population.

Background: Morbidity and mortality vary seasonally. Timing and severity of influenza seasons contribute to those patterns, especially among vulnerable populations such as patients with ESRD. However, the extent to which influenza-like illness (ILI), a syndrome comprising a range of potentially serious respiratory tract infections, contributes to mortality in patients with ESRD has not been quantified.

Trends in Statin Use Among US Adults With Chronic Kidney Disease, 1999-2014.

Background The 2013 American College of Cardiology/American Heart Association cholesterol guidelines recognize cardiovascular disease and diabetes mellitus but not chronic kidney disease ( CKD ) as high-risk conditions warranting statin therapy. Statin use may be lower for adults with CKD compared with adults with conditions that have guideline indications for statin use. Methods and Results We analyzed data from the National Health and Nutrition Examination Surveys from 1999-2002 through 2011-2014 to determine trends in the percentage of US adults ≥20 years of age with and without CKD taking statins.

Adherence to Statin Therapy Among US Adults Between 2007 and 2014.

Background Prior studies suggest that persistence with and adherence to statin therapy is low. Interventions to improve statin persistence and adherence have been developed over the past decade. Methods and Results This was a retrospective cohort study of adults aged ≥21 y with commercial or government health insurance in the MarketScan (Truven Health Analytics) and Medicare databases who initiated statins in 2007-2014 and (1) started treatment after a myocardial infarction (n=201 573), (2) had diabetes mellitus but without coronary heart disease (CHD; n=610 049), or (3) did not have CHD or diabetes mellitus (n=2 244 868).