Clinical Risk Assessment and Prediction in Congenital Heart Disease Across the Lifespan: JACC Scientific Statement.

Congenital heart disease (CHD) comprises a range of structural anomalies, each with a unique natural history, evolving treatment strategies, and distinct long-term consequences. Current prediction models are challenged by generalizability, limited validation, and questionable application to extended follow-up periods. In this JACC Scientific Statement, we tackle the difficulty of risk measurement across the lifespan. We appraise current and future risk measurement frameworks and describe domains of risk specific to CHD. Risk of adverse outcomes varies with age, sex, genetics, era, socioeconomic status, behavior, and comorbidities as they evolve through the lifespan and across care settings. Emerging technologies and approaches promise to improve risk assessment, but there is also need for large, longitudinal, representative, prospective CHD cohorts with multidimensional data and consensus-driven methodologies to provide insight into time-varying risk. Communication of risk, particularly with patients and their families, poses a separate and equally important challenge, and best practices are reviewed.

Utility of Genetically Predicted Lp(a) (Lipoprotein [a]) and ApoB Levels for Cardiovascular Risk Assessment.

BACKGROUND: Current lipid guidelines suggest measurement of Lp(a) (lipoprotein[a]) and ApoB (apolipoprotein B) for atherosclerotic cardiovascular disease risk assessment. Polygenic risk scores (PRSs) for Lp(a) and ApoB may identify individuals unlikely to have elevated Lp(a) or ApoB and thus reduce such suggested testing. METHODS: PRSs were developed using least absolute shrinkage and selection operator regression among 273 222 and 356 958 UK Biobank participants of white British ancestry for Lp(a) and ApoB, respectively, and validated in separate sets of 60 771 UK Biobank and 15 050 European Prospective Investigation into Cancer and Nutrition-Norfolk participants. We then assessed the proportion of participants who, based on these PRSs, were unlikely to benefit from Lp(a) or ApoB measurements, according to current lipid guidelines. RESULTS: In the UK Biobank and European Prospective Investigation into Cancer and Nutrition-Norfolk cohorts, the area under the receiver operating curve for the PRS-predicted Lp(a) and ApoB to identify individuals with elevated Lp(a) and ApoB was at least 0.91 (95% CI, 0.90-0.92) and 0.74 (95% CI, 0.73-0.75), respectively. The Lp(a) PRS and measured Lp(a) showed comparable association with atherosclerotic cardiovascular disease incidence, whereas the ApoB PRS was in general less predictive of atherosclerotic cardiovascular disease risk than measured ApoB. In the context of the European Society of Cardiology/European Atherosclerosis Society lipid guidelines, at a 95% sensitivity to identify individuals with elevated Lp(a) and ApoB levels, at least 54% of Lp(a) and 24% of ApoB testing could be reduced by prescreening with a PRS while maintaining a low false-negative rate. CONCLUSIONS: A substantial proportion of suggested testing for elevated Lp(a) and a modest proportion of testing for elevated ApoB could potentially be reduced by prescreening individuals with PRSs.

Drugs for Prevention and Treatment of Aortic Stenosis: How Close Are We?

Aortic stenosis is one of the most common cardiovascular diseases in the world. Extensive work on the underlying pathophysiology responsible for calcific aortic valve disease and its progression to aortic stenosis has described a complex process involving inflammation, lipid deposition, mineralisation, and genetic factors such as elevated lipoprotein(a). With the advancement of gene silencing technology and development of novel therapeutic agents, we may now be closer than ever to having medical therapies that prevent, or at least slow the progression of aortic stenosis. In this review, we highlight the pathophysiology and risk factors of calcific aortic valve disease, along with current, potential, and emerging novel medical therapies. We also provide potential explanations for the failure of statin trials and suggest new avenues for research and new randomised trials in this area.

Primary Prevention Trial Designs Using Coronary Imaging: A National Heart, Lung, and Blood Institute Workshop.

Coronary artery calcium (CAC) is considered a useful test for enhancing risk assessment in the primary prevention setting. Clinical trials are under consideration. The National Heart, Lung, and Blood Institute convened a multidisciplinary working group on August 26 to 27, 2019, in Bethesda, Maryland, to review available evidence and consider the appropriateness of conducting further research on coronary artery calcium (CAC) testing, or other coronary imaging studies, as a way of informing decisions for primary preventive treatments for cardiovascular disease. The working group concluded that additional evidence to support current guideline recommendations for use of CAC in middle-age adults is very likely to come from currently ongoing trials in that age group, and a new trial is not likely to be timely or cost effective. The current trials will not, however, address the role of CAC testing in younger adults or older adults, who are also not addressed in existing guidelines, nor will existing trials address the potential benefit of an opportunistic screening strategy made feasible by the application of artificial intelligence. Innovative trial designs for testing the value of CAC across the lifespan were strongly considered and represent important opportunities for additional research, particularly those that leverage existing trials or other real-world data streams including clinical computed tomography scans. Sex and racial/ethnic disparities in cardiovascular disease morbidity and mortality, and inclusion of diverse participants in future CAC trials, particularly those based in the United States, would enhance the potential impact of these studies.

Cost-effectiveness of Low-density Lipoprotein Cholesterol Level-Guided Statin Treatment in Patients With Borderline Cardiovascular Risk.

Importance: American College of Cardiology/American Heart Association cholesterol guidelines prioritize primary prevention statin therapy based on 10-year absolute risk (AR10) of atherosclerotic cardiovascular disease (ASCVD). However, given the same AR10, patients with higher levels of low-density lipoprotein cholesterol (LDL-C) experience greater absolute risk reduction from statin therapy. Objectives: To estimate the cost-effectiveness of expanding preventive statin treatment eligibility from standard care to patients at borderline risk (AR10, 5.0%-7.4%) for ASCVD and with high levels of LDL-C and to estimate cost-effectiveness of statin treatment across ranges of age, sex, AR10, and LDL-C levels. Design, Setting, and Participants: This study evaluated 100 simulated cohorts, each including 1 million ASCVD-free survey respondents (50% men and 50% women) aged 40 years at baseline. Cohorts were created by probabilistic sampling of the 1999-2014 US National Health and Nutrition Examination Surveys from the perspective of the US health care sector. The CVD Policy Model microsimulation version projected lifetime health and cost outcomes. Probability of first-ever coronary heart disease or stroke event was estimated by analysis of 6 pooled US cohort studies and recalibrated to match contemporary event rates. Other model variables were derived from national surveys, meta-analyses, and published literature. Data were analyzed from May 15, 2018, through June 10, 2019. Exposures: Four statin treatment strategies were compared: (1) treat all patients with AR10 of at least 7.5%, diabetes, or LDL-C of at least 190 mg/dL (standard care); (2) add treatment for borderline risk and LDL-C levels of 160 to 189 mg/dL; (3) add treatment for borderline risk and LDL-C levels of 130 to 159 mg/dL; and (4) add treatment for remainder of patients with AR10 of at least 5.0%. Statin treatment was also compared with no statin treatment in age, sex, AR10, and LDL-C strata. Main Outcomes and Measures: Lifetime quality-adjusted life-years (QALYs) and costs (2019 US dollars) were projected and discounted 3.0% annually. The primary outcome was the incremental cost-effectiveness ratio. Results: In these 100 simulated cohorts, each with 1 million patients aged 40 years at baseline (50% women and 50% men), adding preventive statins to individuals with borderline AR10 and LDL-C levels of 160 to 189 mg/dL would be cost-saving; further treating borderline AR10 and LDL-C levels of 130 to 159 mg/dL would also be cost-saving; and treating all individuals with AR10 of at least 5.0% would be highly cost-effective ($33 558/QALY) and would prevent the most ASCVD events. Within age, AR10, and sex categories, individuals with higher baseline LDL-C levels gained more QALYs from statin therapy. Cost-effectiveness increased with LDL-C level and AR10. Conclusions and Relevance: In this study, lifetime statin treatment of patients in a hypothetical cohort with borderline ASCVD risk and LDL-C levels of 160 to 189 mg/dL was found to be cost-saving. Results suggest that treating all patients at borderline risk regardless of LDL-C level would likely be highly cost-effective.

Assessment and Management of the Left Atrial Appendage Thrombus in Patients With Nonvalvular Atrial Fibrillation.

BACKGROUND: Intracardiac thrombi arising in the left atrial appendage (LAA) are the principal cause of stroke in nonvalvular atrial fibrillation (AF). Predicting the presence of LAA thrombi is of vital importance in stratifying patients that would need further LAA imaging prior to cardioversion or AF ablation. METHODS: We comprehensively searched PubMed from its inception to November 2017 for randomized controlled trials, cohort and case control studies, as well as for case series on LAA thrombi risk factors, imaging, prevention, and anticoagulation management in atrial fibrillation. RESULTS: A systematic review of the literature identified 106 articles that investigated the presence of LAA thrombi in AF patients. We classified the articles according to topic and reported on: (1) risk factors; (2) diagnostic imaging modalities; (3) prevention strategies before cardioversion; (4) prevention strategies before AF ablation; and (5) management of detected LAA thrombi. CONCLUSIONS: Integration of clinical, biomarker, and imaging risk factors can improve overall prediction for the presence of LAA thrombi, translating into improved patient selection for imaging. The gold standard for the diagnosis of LAA thrombi remains transesophageal echocardiography, although intracardiac ultrasound, cardiac computed tomography, and cardiovascular magnetic imaging are promising alternative modalities. When LAA thrombi are discovered, the treatment regimen remains variable, although direct oral anticoagulants might have efficacy similar to vitamin K antagonists. Future trials will help further elucidate direct oral anticoagulant use for the treatment of LAA thrombi.

Screening Strategies and Primary Prevention Interventions in Relatives of People With Coronary Artery Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Relatives of people with coronary artery disease are at high risk of cardiovascular (CV) disease, but the effect of focused screening and treatment of this population is uncertain. METHODS: We searched the Cochrane Library, Medline, and Embase from inception until June 30, 2014 for articles that described screening strategies and primary prevention interventions targeting family members of patients with coronary artery disease to reduce CV risk. Results were pooled using a random-effects meta-analysis. RESULTS: We identified 18 studies that reported screening strategies and 15 reporting interventions to reduce CV risk. Proband willingness to refer relatives for screening was high (n = 6 studies, pooled rate = 87%; 95% confidence interval [CI], 80%-95%). Studies using a screening strategy in which the relative was contacted by health care professionals reported a pooled participation rate of 88% (95% CI, 78%-99%). The quality of interventional studies was highly variable. Random-effects meta-analysis of the highest quality randomized studies (n = 6) consisting of a specialized risk factor intervention compared with usual care was consistent with modest improvements in low-density lipoprotein cholesterol control (-0.18 mmol/L low-density lipoprotein cholesterol, 95% CI, -0.35 to -0.001; P = 0.048). Improvements in diet, smoking rates, exercise, and blood pressure were also observed with active intervention; however, reported outcomes were heterogeneous precluding a formal meta-analysis. CONCLUSIONS: Screening strategies that target family members, particularly when led by a health care professional, achieve a high participation rate. Although the available evidence is of variable quality, interventions that target individuals with a family history of coronary artery disease appear to be feasible and might be effective in improving certain risk factors or health behaviours but their long-term CV benefits remain uncertain.

Limitations in the conventional assessment of the incremental value of predictors of cardiovascular risk.

PURPOSE OF REVIEW: Whether a factor significantly increases the area under the curve (AUC) of a receiver operating characteristic analysis has become the standard test of its utility. Thus, in many studies, apolipoprotein B and LDL particle number have not increased the AUC significantly beyond that produced by the conventional markers, and guideline groups have concluded on this basis that they should not be added to routine clinical practice. This article demonstrates this conclusion to be invalid. RECENT FINDINGS: In conventional analyses, no distinctions have been drawn as to whether a novel predictor is causal or whether it is highly correlated with other markers already included in the risk algorithm. However, correlation among the markers will profoundly affect the incremental effect of a factor on the AUC. This distinction is particularly critical for factors that have been shown to play a causal role in the production of clinical event. Accordingly, the AUC approach is valid to determine the total discriminatory ability of a set of variables but is not appropriate to allocate attributable risk among the members of the set. SUMMARY: For correlated predictors that describe different aspects of the same variable such as non-HDL-C and apoB or LDL-C and LDL particle number, discordance analysis offers a simple valid alternative to capture and compare the independent information contained by each predictor.

Apolipoprotein B improves risk assessment of future coronary heart disease in the Framingham Heart Study beyond LDL-C and non-HDL-C.

AIMS: Analyses using conventional statistical methodologies have yielded conflicting results as to whether low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) or apolipoprotein B (apoB) is the best marker of the apoB-associated risk of coronary heart disease. The aim of this study was to determine the additional value of apoB beyond LDL-C or non-HDL-C as a predictor of coronary heart disease. METHODS AND RESULTS: For each patient from the Framingham Offspring Cohort aged 40-75 years (n = 2966), we calculated the extent to which the observed apoB differed from the expected apoB based on their LDL-C or non-HDL-C. We added this difference to a Cox model predicting new onset coronary heart disease over a maximum of 20 years adjusting for standard risk factors plus LDL-C or non-HDL. The difference between observed and expected apoB over LDL-C or non-HDL-C was highly prognostic of future coronary heart disease events: adjusted hazard ratios 1.26 (95% confidence interval: 1.15, 1.37) and 1.20 (1.11, 1.29), respectively, for each standard deviation increase beyond expected apoB levels. When this difference between observed and expected apoB was added to standard coronary heart disease prediction models including LDL-C or non-HDL-C, prediction improved significantly (likelihood ratio test p-values <0.0001) and discrimination c-statistics increased from 0.72 to 0.73. The corresponding relative integrated discrimination improvements were 11% and 8%, respectively. CONCLUSIONS: apoB improves risk assessment of future coronary heart disease events over and beyond LDL-C or non-HDL-C, which is consistent with coronary risk being more closely related to the number of atherogenic apoB particles than to the mass of cholesterol within them.

Comparison of coronary calcium screening versus broad statin therapy for patients at intermediate cardiovascular risk.

Net reclassification has become widely accepted as a method to demonstrate whether new diagnostic technologies add significantly to the discrimination of risk. However, more accurate categorization of risk does not necessarily result in a better clinical outcome. This study examined whether coronary artery calcium, a technology that improves net reclassification in patients at intermediate risk for cardiovascular events, is superior to a strategy that calls for broader intervention with statin therapy in these patients. To do so, the clinical impact and costs of 2 intervention regimens on outcome in the Multi-Ethnic Study of Atherosclerosis (MESA) were calculated based on the known efficacy of statins. Intervention 1 involved treatment of all subjects at conventional intermediate risk with moderate-dose stain, whereas intervention 2 involved moderate- and high-dose statin therapy, respectively, of those remaining at intermediate risk and those reassigned to high risk after reclassification by coronary artery calcium. The 2 strategies would decrease clinical events by 23% and would produce net savings. However, these would be greater with the broad statin prevention strategy than with the coronary calcium reclassification strategy ($732,152 vs $288,336, respectively). In conclusion, even in the short term, the broad statin prevention strategy would be at least as effective in decreasing clinical events but with greater net savings than a prevention strategy using coronary calcium screening.

Impact of restrictive prescription plans on heart failure medication use.

BACKGROUND: Prescription plans frequently use restrictive strategies to control drug expenditures. Increased restrictions may reduce access to evidence-based therapy among patients with chronic disease. We sought to evaluate the impact of increased restrictions on medication use among heart failure (HF) patients. METHODS AND RESULTS: We conducted a population-based cohort study of administrative data from 3 Canadian provinces. During 1998 to 2001, Quebec (QC) had a minimally restrictive plan, whereas Ontario (ON) and British Columbia (BC) had more restrictive prescription plans. We evaluated drug use at 30 days of discharge stratified by prescription plan. Provincial rates of filled prescriptions for HF drugs in QC, ON, and BC were 62%, 58%, and 47% for angiotensin-converting enzyme inhibitors; 34%, 22%, and 16% for beta-blockers; 9%, 5%, and 3% for angiotensin receptor blockers; and 79%, 76%, and 62% for loop diuretics, respectively. In multivariate analyses, patients residing in provinces with restrictive plans were less likely to be prescribed drugs that were restricted, such as beta-blockers (odds ratio, 0.53; 95% CI, 0.46 to 0.60; 0.36, 0.29 to 0.44, for ON and BC, respectively) and angiotensin receptor blockers (0.50, 0.45 to 0.56; 0.38, 0.32 to 0.46, for ON and BC, respectively), than drugs with no restrictions, such as loop diuretics (0.81, 0.74 to 0.88; 0.40, 0.36 to 0.45, for ON and BC, respectively) and angiotensin-converting enzyme inhibitors (0.80, 0.75 to 0.86; 0.47, 0.43 to 0.52, for ON and BC, respectively). CONCLUSIONS: Among HF patients, residing in a province with a more restrictive prescription plan may be associated with lower use of restricted HF medications over and above the expected regional differences in HF drug use across provinces.