Biallelic variants in POPDC2 cause a novel autosomal recessive syndrome presenting with cardiac conduction defects and variable hypertrophic cardiomyopathy.

POPDC2 encodes for the Popeye domain-containing protein 2 which has an important role in cardiac pacemaking and conduction, due in part to its cAMP-dependent binding and regulation of TREK-1 potassium channels. Loss of Popdc2 in mice results in sinus pauses and bradycardia and morpholino knockdown of popdc2 in zebrafish results in atrioventricular (AV) block. We identified bi-allelic variants in POPDC2 in 4 families that presented with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects and hypertrophic cardiomyopathy. Using homology modelling we show that the identified POPDC2 variants are predicted to diminish the ability of POPDC2 to bind cAMP. In in vitro electrophysiological studies we demonstrated that, while co-expression of wild-type POPDC2 with TREK-1 increased TREK-1 current density, POPDC2 variants found in the patients failed to increase TREK-1 current density. While patient muscle biopsy did not show clear myopathic disease, it showed significant reduction of the expression of both POPDC1 and POPDC2, suggesting that stability and/or membrane trafficking of the POPDC1-POPDC2 complex is impaired by pathogenic variants in any of the two proteins. Single-cell RNA sequencing from human hearts demonstrated that co-expression of POPDC1 and 2 was most prevalent in AV node, AV node pacemaker and AV bundle cells. Sinoatrial node cells expressed POPDC2 abundantly, but expression of POPDC1 was sparse. Together, these results concur with predisposition to AV node disease in humans with loss-of-function variants in POPDC1 and POPDC2 and presence of sinus node disease in POPDC2, but not in POPDC1 related disease in human. Using population-level genetic data of more than 1 million individuals we showed that none of the familial variants were associated with clinical outcomes in heterozygous state, suggesting that heterozygous family members are unlikely to develop clinical manifestations and therefore might not necessitate clinical follow-up. Our findings provide evidence for POPDC2 as the cause of a novel Mendelian autosomal recessive cardiac syndrome, consistent with previous work showing that mice and zebrafish deficient in functional POPDC2 display sinus and AV node dysfunction.

Contribution of Clinical Trial Event Data by Data Source: A Prespecified Analysis of the ADAPTABLE Randomized Clinical Trial.

Importance: Pragmatic randomized clinical trials (RCTs) often use multiple data sources to examine clinical events, but the relative contribution of data sources to clinical end-point rates is understudied. Objective: To assess the contribution of data sources (electronic health records [EHRs], public/private insurance claims, and/or participant-reported data) to clinical end points among ADAPTABLE participants who had available data. Design, Setting, and Participants: The ADAPTABLE study was an open-label, pragmatic RCT from April 2016 through June 2019 conducted in research networks within clinical practice. Participants had existing atherosclerotic cardiovascular disease and available data to analyze. The characteristics of patients by combinations of data source availability were compared to examine the contribution of each of the data sources to end-point ascertainment. Data for this prespecified analysis were examined from January 2022 to June 2023. Exposures: Randomized exposure to 81 mg or 325 mg of aspirin daily. Main Outcomes and Measures: Number of events for the primary end point (composite of death, hospitalization for myocardial infarction, and hospitalization for stroke) that were contributed by EHR or claims data and then number of events contributed by each additional data source. Results: Of 15 006 participants randomized with at least 1 other source of data available beyond participant-reported data, there were 8756 (58.3%) with participant-reported and EHR data; 4291 (28.6%) with participant-reported, EHR, and claims data; 1412 (9.4%) with EHR-only data; 262 (1.7%) with participant-reported and claims data; 202 (1.3%) with EHR and claims data; and 83 (0.6%) with claims-only data. Participants with EHR-only data were younger (median age, 63.7 years; IQR, 55.8-71.4) compared with the other groups (range, 65.6-71.9 years). Among participants with both EHR and claims data, with or without participant-reported data (n = 4493), for each outcome, most events (92%-100%) were identified in the EHR or in claims data. For all clinical end points, participant-reported data contributed less than 10% of events not otherwise available from claims or EHR data. Conclusions and Relevance: In this analysis of a pragmatic RCT, claims and EHR data provided the most clinical end-point data when compared with participant-reported events. These findings provide a framework for collecting end points in pragmatic clinical trials. Further work is needed to understand the data source combinations that most effectively provide clinical end-point data in RCTs.

Association of Short-Term Increases in Ambient Fine Particulate Matter With Hospitalization for Asthma or COPD During Wildfire Season and Other Time Periods.

BACKGROUND: Short-term increases in air pollution are associated with poor asthma and COPD outcomes. Short-term elevations in fine particulate matter (PM2.5) due to wildfire smoke are becoming more common. RESEARCH QUESTION: Are short-term increases in PM2.5 and ozone in wildfire season and in winter inversion season associated with a composite of emergency or inpatient hospitalization for asthma and COPD? STUDY DESIGN AND METHODS: Case-crossover analyses evaluated 63,976 and 18,514 patients hospitalized for primary discharge diagnoses of asthma and COPD, respectively, between January 1999 and March 2022. Patients resided on Utah's Wasatch Front where PM2.5 and ozone were measured by Environmental Protection Agency-based monitors. ORs were calculated using Poisson regression adjusted for weather variables. RESULTS: Asthma risk increased on the same day that PM2.5 increased during wildfire season (OR, 1.057 per + 10 µg/m3; 95% CI, 1.019-1.097; P = .003) and winter inversions (OR, 1.023 per +10 µg/m3; 95% CI, 1.010-1.037; P = .0004). Risk decreased after 1 week, but during wildfire season risk rebounded at a 4-week lag (OR, 1.098 per +10 µg/m3; 95% CI, 1.033-1.167). Asthma risk for adults during wildfire season was highest in the first 3 days after PM2.5 increases, but for children, the highest risk was delayed by 3 to 4 weeks. PM2.5 exposure was weakly associated with COPD hospitalization. Ozone exposure was not associated with elevated risks. INTERPRETATION: In a large urban population, short-term increases in PM2.5 during wildfire season were associated with asthma hospitalization, and the effect sizes were greater than for PM2.5 during inversion season.

Periodic Fasting and Acute Cardiac Events in Patients Evaluated for COVID-19: An Observational Prospective Cohort Study.

BACKGROUND: Periodic fasting was previously associated with greater longevity and a lower incidence of heart failure (HF) in a pre-pandemic population. In patients with coronavirus disease 2019 (COVID-19), periodic fasting was associated with a lower risk of death or hospitalization. This study evaluated the association between periodic fasting and HF hospitalization and major adverse cardiovascular events (MACEs). METHODS: Patients enrolled in the INSPIRE registry from February 2013 to March 2020 provided periodic fasting information and were followed into the pandemic (n = 5227). Between March 2020 and February 2023, N = 2373 patients were studied, with n = 601 COVID-positive patients being the primary study population (2836 had no COVID-19 test; 18 were excluded due to fasting <5 years). A Cox regression was used to evaluate HF admissions, MACEs, and other endpoints through March 2023, adjusting for covariables, including time-varying COVID-19 vaccination. RESULTS: In patients positive for COVID-19, periodic fasting was reported by 180 (30.0% of 601), who periodically fasted over 43.1 ± 19.2 years (min: 7, max: 83). HF hospitalization (n = 117, 19.5%) occurred in 13.3% of fasters and 22.1% of non-fasters [adjusted hazard ratio (aHR) = 0.63, CI = 0.40, 0.99; p = 0.044]. Most HF admissions were exacerbations, with a prior HF diagnosis in 111 (94.9%) patients hospitalized for HF. Fasting was also associated with a lower MACE risk (aHR = 0.64, CI = 0.43, 0.96; p = 0.030). In n = 1772 COVID-negative patients (29.7% fasters), fasting was not associated with HF hospitalization (aHR = 0.82, CI = 0.64, 1.05; p = 0.12). In COVID-positive and negative patients combined, periodic fasting was associated with lower mortality (aHR = 0.60, CI = 0.39, 0.93; p = 0.021). CONCLUSIONS: Routine periodic fasting was associated with less HF hospitalization in patients positive for COVID-19.

Start codon variant in LAG3 is associated with decreased LAG-3 expression and increased risk of autoimmune thyroid disease.

Autoimmune thyroid disease (AITD) is a common autoimmune disease. In a GWAS meta-analysis of 110,945 cases and 1,084,290 controls, 290 sequence variants at 225 loci are associated with AITD. Of these variants, 115 are previously unreported. Multiomics analysis yields 235 candidate genes outside the MHC-region and the findings highlight the importance of genes involved in T-cell regulation. A rare 5'-UTR variant (rs781745126-T, MAF = 0.13% in Iceland) in LAG3 has the largest effect (OR = 3.42, P = 2.2 × 10-16) and generates a novel start codon for an open reading frame upstream of the canonical protein translation initiation site. rs781745126-T reduces mRNA and surface expression of the inhibitory immune checkpoint LAG-3 co-receptor on activated lymphocyte subsets and halves LAG-3 levels in plasma among heterozygotes. All three homozygous carriers of rs781745126-T have AITD, of whom one also has two other T-cell mediated diseases, that is vitiligo and type 1 diabetes. rs781745126-T associates nominally with vitiligo (OR = 5.1, P = 6.5 × 10-3) but not with type 1 diabetes. Thus, the effect of rs781745126-T is akin to drugs that inhibit LAG-3, which unleash immune responses and can have thyroid dysfunction and vitiligo as adverse events. This illustrates how a multiomics approach can reveal potential drug targets and safety concerns.

Contemporary Predictors of Major Adverse Cardiovascular Events Following Percutaneous Coronary Intervention: A Nationally Representative US Sample.

Background: Patient outcomes after percutaneous coronary intervention (PCI) have improved over the last 30 years due to better techniques, therapies, and care processes. This study evaluated contemporary predictors of post-PCI major adverse cardiovascular events (MACE) and summarized risk in a parsimonious risk prediction model. Methods: The Cardiovascular Patient-Level Analytical Platform (CLiPPeR) is an observational dataset of baseline variables and longitudinal outcomes from the American College of Cardiology's CathPCI Registry® and national claims data. Cox regression was used to evaluate 2-6 years of patient follow-up (mean: 2.56 years), ending in December 2017, after index PCI between 2012 and 2015 (N = 1,450,787), to examine clinical and procedural predictors of MACE (first myocardial infarction, stroke, repeat PCI, coronary artery bypass grafting, and mortality). Cox analyses of post-PCI MACE were landmarked 28 days after index PCI. Results: Overall, 12.4% (n = 179,849) experienced MACE. All variables predicted MACE, with cardiogenic shock, cardiac arrest, four diseased coronary vessels, and chronic kidney disease having hazard ratios (HRs) ≥ 1.50. Other major predictors of MACE were in-hospital stroke, three-vessel disease, anemia, heart failure, and STEMI presentation. The index revascularization and discharge prescription of aspirin, P2Y12 inhibitor, and lipid-lowering medication had HR ≤ 0.67. The primary Cox model had c-statistic c = 0.761 for MACE versus c = 0.701 for the parsimonious model and c = 0.752 for the parsimonious model plus treatment variables. Conclusions: In a nationally representative US sample of post-PCI patients, predictors of longitudinal MACE risk were identified, and a parsimonious model efficiently encapsulated them. These findings may aid in assessing care processes to further improve care post-PCI outcomes.

Coronary Calcium Is Elevated in Patients with Myocardial Infarction without Standard Modifiable Risk Factors.

Objectives: Recent reports have highlighted myocardial infarction (MI) patients without standard modifiable risk factors (SMRF), noting them to be surprisingly common and to have a substantial risk of adverse outcomes. The objective of this study was to address the challenge of identifying at-risk patients without SMRF and providing preventive therapy. Methods: Patients presenting between 2001 and 2021 to Intermountain Health catheterization laboratories with a diagnosis of MI were included if they also had a coronary artery calcium (CAC) scan by computed tomography within 2 years. SMRF were defined as a clinical diagnosis or treatment of hypertension, hyperlipidemia, diabetes, or smoking. The co-primary endpoints in SMRF-less patients were: (1) proportion of patients with an elevated (>50%ile) CAC score, and (2) an indication for statin therapy (i.e., CAC ≥ 100 AU or ≥75%ile). The 60-day and long-term major adverse cardiovascular events were determined. A comparison set included MI patients with SMRF. Results: We identified 429 MI patients with a concurrent CAC scan, of which 60 had no SMRF. SMRF status did not distinguish most risk factors or interventions. No-SMRF patients had a high CAC prevalence and percentile (82% ≥ 50%ile; median, 80%ile), and 77% met criteria for preventive therapy. As expected, patients with SMRF had high CAC scores and percentiles. Outcomes were more favorable for No-SMRF status and for lower CAC scores. Conclusions: Patients without SMRF presenting with an MI have a high prevalence and percentile of CAC. Wider application of CAC scans, including in those without SMRF, is promising as a method to identify an additional at-risk population for MI and to provide primary preventive therapy.

Framework of the strengths and challenges of clinically integrated trials: An expert panel report.

The limitations of the explanatory clinical trial framework include the high expense of implementing explanatory trials, restrictive entry criteria for participants, and redundant logistical processes. These limitations can result in slow evidence generation that is not responsive to population health needs, yielding evidence that is not generalizable. Clinically integrated trials, which integrate clinical research into routine care, represent a potential solution to this challenge and an opportunity to support learning health systems. The operational and design features of clinically integrated trials include a focused scope, simplicity in design and requirements, the leveraging of existing data structures, and patient participation in the entire trial process. These features are designed to minimize barriers to participation and trial execution and reduce additional research burdens for participants and clinicians alike. Broad adoption and scalability of clinically integrated trials are dependent, in part, on continuing regulatory, healthcare system, and payer support. This analysis presents a framework of the strengths and challenges of clinically integrated trials and is based on a multidisciplinary expert "Think Tank" panel discussion that included representatives from patient populations, academia, non-profit funding agencies, the U.S. Food and Drug Administration, and industry.

GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis.

Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson's disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.

Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.

We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.

Age and Aspirin Dosing in Secondary Prevention of Atherosclerotic Cardiovascular Disease.

BACKGROUND: In patients with atherosclerotic cardiovascular disease, increasing age is concurrently associated with higher risks of ischemic and bleeding events. The objectives are to determine the impact of aspirin dose on clinical outcomes according to age in atherosclerotic cardiovascular disease. METHODS AND RESULTS: In the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) trial, patients with atherosclerotic cardiovascular disease were randomized to daily aspirin doses of 81 mg or 325 mg. The primary effectiveness end point was death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke. The primary safety end point was hospitalization for bleeding requiring transfusion. A total of 15 076 participants were randomized to aspirin 81 mg (n=7540) or 325 mg (n=7536) daily (median follow-up: 26.2 months; interquartile range: 19.0-34.9 months). Median age was 67.6 years (interquartile range: 60.7-73.6 years). Among participants aged <65 years (n=5841 [38.7%]), a primary end point occurred in 226 (7.54%) in the 81 mg group, and in 191 (6.80%) in the 325 mg group (adjusted hazard ratio [HR], 1.23 [95% CI, 1.01-1.49]). Among participants aged ≥65 years (n=9235 [61.3%]), a primary end point occurred in 364 (7.12%) in the 81 mg group, and in 378 (7.96%) in the 325 mg group (adjusted HR, 0.95 [95% CI, 0.82-1.10]). The age-dose interaction was not significant (P=0.559). There was no significant interaction between age and the randomized aspirin dose for the secondary effectiveness and the primary safety bleeding end points (P>0.05 for all). CONCLUSIONS: Age does not modify the impact of aspirin dosing (81 mg or 325 mg daily) on clinical end points in secondary prevention of atherosclerotic cardiovascular disease.

Obesity Variants in the GIPR Gene Are not Associated With Risk of Fracture or Bone Mineral Density.

CONTEXT: It is not clear if antagonizing the GIP (glucose-dependent insulinotropic polypeptide) receptor (GIPR) for treatment of obesity is likely to increase the risk of fractures, or to lower bone mineral density (BMD) beyond what is expected with rapid weight loss. OBJECTIVE: The objective of this study was to investigate the risk of fracture and BMD of sequence variants in GIPR that reduce the activity of the GIP receptor and have been associated with reduced body mass index (BMI). METHODS: We analyzed the association of 3 missense variants in GIPR, a common variant, rs1800437 (p.Glu354Gln), and 2 rare variants, rs139215588 (p.Arg190Gln) and rs143430880 (p.Glu288Gly), as well as a burden of predicted loss-of-function (LoF) variants with risk of fracture and with BMD in a large meta-analysis of up to 1.2 million participants. We analyzed associations with fractures at different skeletal sites in the general population: any fractures, hip fractures, vertebral fractures and forearm fractures, and specifically nonvertebral and osteoporotic fractures in postmenopausal women. We also evaluated associations with BMD at the lumbar spine, femoral neck, and total body measured with dual-energy x-ray absorptiometry (DXA), and with BMD estimated from heel ultrasound (eBMD). RESULTS: None of the 3 missense variants in GIPR was significantly associated with increased risk of fractures or with lower BMD. Burden of LoF variants in GIPR was not associated with fractures or with BMD measured with clinically validated DXA, but was associated with eBMD. CONCLUSION: Missense variants in GIPR, or burden of LoF variants in the gene, are not associated with risk of fractures or with lower BMD.

Variants at the Interleukin 1 Gene Locus and Pericarditis.

Importance: Recurrent pericarditis is a treatment challenge and often a debilitating condition. Drugs inhibiting interleukin 1 cytokines are a promising new treatment option, but their use is based on scarce biological evidence and clinical trials of modest sizes, and the contributions of innate and adaptive immune processes to the pathophysiology are incompletely understood. Objective: To use human genomics, transcriptomics, and proteomics to shed light on the pathogenesis of pericarditis. Design, Setting, and Participants: This was a meta-analysis of genome-wide association studies of pericarditis from 5 countries. Associations were examined between the pericarditis-associated variants and pericarditis subtypes (including recurrent pericarditis) and secondary phenotypes. To explore mechanisms, associations with messenger RNA expression (cis-eQTL), plasma protein levels (pQTL), and CpG methylation of DNA (ASM-QTL) were assessed. Data from Iceland (deCODE genetics, 1983-2020), Denmark (Copenhagen Hospital Biobank/Danish Blood Donor Study, 1977-2022), the UK (UK Biobank, 1953-2021), the US (Intermountain, 1996-2022), and Finland (FinnGen, 1970-2022) were included. Data were analyzed from September 2022 to August 2023. Exposure: Genotype. Main Outcomes and Measures: Pericarditis. Results: In this genome-wide association study of 4894 individuals with pericarditis (mean [SD] age at diagnosis, 51.4 [17.9] years, 2734 [67.6%] male, excluding the FinnGen cohort), associations were identified with 2 independent common intergenic variants at the interleukin 1 locus on chromosome 2q14. The lead variant was rs12992780 (T) (effect allele frequency [EAF], 31%-40%; odds ratio [OR], 0.83; 95% CI, 0.79-0.87; P = 6.67 × 10-16), downstream of IL1B and the secondary variant rs7575402 (A or T) (EAF, 45%-55%; adjusted OR, 0.89; 95% CI, 0.85-0.93; adjusted P = 9.6 × 10-8). The lead variant rs12992780 had a smaller odds ratio for recurrent pericarditis (0.76) than the acute form (0.86) (P for heterogeneity = .03) and rs7575402 was associated with CpG methylation overlapping binding sites of 4 transcription factors known to regulate interleukin 1 production: PU.1 (encoded by SPI1), STAT1, STAT3, and CCAAT/enhancer-binding protein ß (encoded by CEBPB). Conclusions and Relevance: This study found an association between pericarditis and 2 independent sequence variants at the interleukin 1 gene locus. This finding has the potential to contribute to development of more targeted and personalized therapy of pericarditis with interleukin 1-blocking drugs.

Impact of Statin Therapy in Heart Failure Patients: Results of a Large Real-World Experience.

Background: The use of statins in patients with heart failure (HF) is controversial. In patients without HF, statins reduce atherosclerotic cardiovascular disease (ASCVD) risk, including HF-related events. However, in some large studies, no benefit was seen in statin-treated HF patients. Objectives: The purpose of this study was to determine the impact of statin therapy in HF with reduced ejection fraction (HFrEF). Methods: Intermountain Healthcare medical records identified patients with a HF diagnosis and an ejection fraction of ≤40%. Patients prescribed and not prescribed a statin were compared for major adverse cardiovascular events (MACE) (death, myocardial infarction, stroke) (median of 4.5 years follow-up). Statin use was defined as use at or after a HF diagnosis but at least 60 days before MACE or end of follow-up. Cox proportional hazards regression was used to determine the relationship between statin use and outcomes. Results: A total of 15,010 patients (n = 9,641 [64%] on statins) were studied. Statin use was associated with more frequent ASCVD risk factors yet a lower risk of MACE risk (adjusted HR: 0.53; 95% CI: 0.51-0.56; P < 0.0001). Benefit was similar for primary and secondary prevention patients and for prior and new statin prescriptions. Using time-varying hazard ratio analysis, the longer the patient was on a statin, the greater the reduction in risk of MACE (P < 0.0001). Conclusions: These results suggest a potential benefit of selective statin use in the real-world management of HFrEF patients with ASCVD or at high ASCVD risk.

Impact of Active vs Passive Statin Selection for Primary Prevention: The CorCal Vanguard Trial.

Background: Statins can improve outcomes in high-risk primary prevention populations. However, application in clinical practice has lagged. Objectives: The objective of this study was to compare an active vs a passive strategy (ie, usual care) to statin prescription for primary prevention of atherosclerotic cardiovascular disease (ASCVD). Methods: A total of 3,770 patients ≥50 years of age without a history of ASCVD or statin use were invited to enroll in CorCal, with 601 consenting to participate. These patients were randomized 1:1 to statin initiation guided by the pooled cohort equation or by coronary artery calcium scoring (CACS). Outcomes (2.8-year follow-up) compared patients managed actively vs passively (randomly invited but declined or did not respond). Results: Patient demographics were well matched. Statin recommendation was common among enrolled patients (41.7%). During follow-up, 25.3% of active patients were taking a statin vs 9.8% managed passively (P < 0.0001). Active patients had more lipid panels (median 2.0 vs 1.0), lower low-density lipoprotein cholesterol (109 vs 117 mg/dL) (both P < 0.0001), and a low rate of major adverse cardiovascular events during follow-up (0.6% vs 1.0%, P = 0.47). Statistical comparisons included t-tests, chi-squared tests, nonparametric tests, and time-to-event tests as appropriate. Conclusions: An active approach to statin selection for primary ASCVD prevention identified a large treatment opportunity and led to over twice as many patients on statins compared to passive (usual care) management. A large CorCal Outcomes Trial is underway to more definitively assess the impact on outcomes of active management of statins for primary prevention.