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Supplemental Digital Content is available in the text., Background: To optimize preventive strategies for coronary heart disease (CHD), it is essential to understand and appropriately quantify the contribution of its key risk factors. Our objective was to compare the associations of key modifiable CHD risk factors—specifically lipids, systolic blood pressure (SBP), diabetes mellitus, and smoking—with incident CHD events based on their prognostic performance, attributable risk fractions, and treatment benefits, overall and by age. Methods: Pooled participant-level data from 4 observational cohort studies sponsored by the National Heart, Lung, and Blood Institute were used to create a cohort of 22 626 individuals aged 45 to 84 years who were initially free of cardiovascular disease. Individuals were followed for 10 years from baseline evaluation for incident CHD. Proportional hazards regression was used to estimate metrics of prognostic model performance (likelihood ratio, C index, net reclassification, discrimination slope), hazard ratios, and population attributable fractions for SBP, non–high-density lipoprotein cholesterol (non–HDL-C), diabetes mellitus, and smoking. Expected absolute risk reductions for antihypertensive and lipid-lowering treatment were assessed. Results: Age, sex, and race capture 63% to 80% of the prognostic performance of cardiovascular risk models. In contrast, adding either SBP, non–HDL-C, diabetes mellitus, or smoking to a model with other risk factors increases the C index by only 0.004 to 0.013. However, primordial prevention could have a substantial effect as demonstrated by population attributable fractions of 28% for SBP≥130 mm Hg and 17% for non–HDL-C≥130 mg/dL. Similarly, lowering the SBP of all individuals to

Introduction: Studies using electronic health record (EHR) data often have a limited number of years available for analysis. There is a trade off between the look back period length used to define baseline characteristics and follow up duration used to define outcomes. Objective: Quantify the impact of 6, 12, and 24 month look back periods on the association between diabetes (DM) and subsequent cardiovascular (CV) events using EHR data alone and in combination with Medicare claims. Methods: EHR data from an academic health system and a federally qualified health center from 2009-2014 were linked to Medicare claims data. Eligibility criteria were age ≥65 years, Durham County address, 24 months of continuous enrollment after first claim, EHR encounter in the 2011 index year, and no history of cardiovascular disease (CVD) in the 24 months prior to the index date (i.e., look back period). DM was defined using EHR ICD-9 codes, HbA1c ≥6.5%, or glucose lowering medication, and using claims based diagnosis codes or glucose lowering medication. The outcome was a major CV event (myocardial infarction, stroke, or cardiac procedure) defined by diagnosis or procedure codes. Hazard ratios (HR) compared time to the outcome between patients with and without DM. Results: In 5473 patients, mean age was 77 years, 67% were female and 28% were Black. The prevalence of DM using EHR data only increased with a longer look back period (6 months [19%]; 12 months [21%]; 24 months [23%]) but was less than the prevalence using all available data from EHRs and claims together (28%) (Table 1A). Shorter look back periods resulted in higher HRs (6 month HR=1.64) as compared to HRs from longer look back periods (24 month HR=1.41) using EHR data alone or all available data from the EHR and claims together (HR=1.43) (Table 1B). Conclusions: To avoid over estimating associations, studies of CVD using EHR data to identify baseline conditions may want to use 12-24 month look back periods in the absence of additional administrative data. This may also lead to a shorter follow-up period.

Introduction: Influenza infection is associated with increased morbidity and mortality in patients with cardiovascular disease (CVD). We assessed the effects of influenza vaccine on mortality and cardiovascular outcomes in patients with CVD. Hypothesis: Influenza vaccination in those with CVD is associated with a reduction in mortality and major adverse cardiovascular events (MACE). Methods: We searched PubMed, EMBASE, and Cochrane library through January 2020 for randomized-controlled trials (RCTs) and observational studies assessing effects of influenza vaccine on mortality and cardiovascular outcomes in patients with CVD. Estimates were reported as random effects risk ratios (RR) with 95% confidence intervals (CI). Analyses were stratified by study design into RCT and observational studies. Results: Overall, 16 studies (n=237,058) encompassing 4 RCTs (n=1,667) and 12 observational studies (n=235,391) were included. The mean age was 69.2±7.01; 36.6% were female, 65.1% had hypertension, 31.1% had diabetes, and 23.4% were smokers. The median follow-up duration was 19.5 (IQR, 12, 43.3) months. Influenza vaccine was associated with a lower risk of all-cause mortality (RR, 0.72 [95% CI, 0.59-0.89], pFigure 1A ), cardiovascular mortality (RR, 0.82 [95% CI, 0.80-0.84], pFigure 1B ), though the association with myocardial infarction was not statistically significant (RR, 0.73 [95% CI, 0.50-1.07]; p=0.10). These finding were consistent across randomized and observational studies. Conclusions: This meta-analysis suggests that both randomized and observational data support the use of influenza vaccine in adults with CVD to reduce mortality and MACE events. Efforts to improve utilization of influenza vaccine in this population should continue to reap survival benefits.

Background: The ACC/AHA Pooled Cohort Equations (PCE), derived using data from adults ages 40-79, have not been evaluated for accuracy among older adults. Methods: We evaluated 2,667 adults aged ≥75 years without known ASCVD in the NIH pooled cohorts (Framingham, Framingham offspring, MESA, & CHS), stratified by number of major risk factors [smoking, diabetes, lipids (LDL≥130 mg/dL or on lipid-lowering therapy), and BP (≥140/90 mmHg or on BP medication)]. Observed vs. predicted 5-year ASCVD event rates were compared across strata. We also evaluated 5-year PCE model performance overall. Results: At the group level, the PCE somewhat overestimated risk across all strata in Kaplan Meier analysis: observed versus expected was 7.0% vs. 11.0%, (p=0.005) for those with no risk factors (N=429), 12.5% vs. 15.4%, (p Conclusion: The PCE can be used to risk-stratify older adults. However, it may over-predict risk, especially in those at the top quartile of risk.

Objectives: In young adults, which blood pressure (BP) patterns, determined over multiple clinic visits, are most associated with future risk for cardiovascular disease (CVD) and all-cause mortality remains unclear. We determined BP patterns during young adulthood most associated with CVD events and all-cause mortality by middle age. BP patterns included average systolic BP (SBP)/diastolic BP (DBP) levels, cumulative exposure to SBP/DBP, visit-to-visit SBP/DBP variability, and average annual change in SBP/DBP. Methods: We analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, which enrolled 5115 adults aged 18-30 years from 1985-1986, with up to 30 years of follow-up (through 2015). BP patterns were evaluated with measurements at Year 0 [baseline], and 2, 5, 7, and 10 years following baseline. We estimated visit-to-visit BP variability as variability independent of the mean (VIM). Average annual change of BP from the Year 0 to Year 10 exams was calculated using linear regression. Cox proportional hazards models were used to assess the associations between BP patterns and adjudicated CVD events (coronary heart disease, stroke, heart failure, and other vascular disease) and all-cause mortality. Results: At Year 10, the mean±standard deviation (SD) age of the 3,394 participants was 35.1±3.6 years, 46% were African American, 56% were female, and only 3% were taking antihypertensive medication. Cumulative exposure to SBP and average SBP levels were highly correlated (Pearson’s correlation = 0.94). Over a median follow-up of 19.2 years, 162 CVD events and 181 deaths occurred. Average SBP and DBP levels and VIM of SBP were associated with increased CVD risk (see table), with no interaction by race or sex (each p>0.4). Only VIM of SBP was associated with all-cause mortality. Conclusions: Among young adults, the assessment of visit-to-visit SBP variability in addition to average SBP and DBP levels can help identify young adults who have an increased CVD risk and all-cause mortality by middle age.

Background— Many young adults with moderate hyperlipidemia do not meet statin treatment criteria under the new American Heart Association/American College of Cardiology cholesterol guidelines because they focus on 10-year cardiovascular risk. We evaluated the association between years of exposure to hypercholesterolemia in early adulthood and future coronary heart disease (CHD) risk. Methods and Results— We examined Framingham Offspring Cohort data to identify adults without incident cardiovascular disease to 55 years of age (n=1478), and explored the association between duration of moderate hyperlipidemia (non–high-density lipoprotein cholesterol≥160 mg/dL) in early adulthood and subsequent CHD. At median 15-year follow-up, CHD rates were significantly elevated among adults with prolonged hyperlipidemia exposure by 55 years of age: 4.4% for those with no exposure, 8.1% for those with 1 to 10 years of exposure, and 16.5% for those with 11 to 20 years of exposure ( P Conclusions— Cumulative exposure to hyperlipidemia in young adulthood increases the subsequent risk of CHD in a dose-dependent fashion. Adults with prolonged exposure to even moderate elevations in non–high-density lipoprotein cholesterol have elevated risk for future CHD and may benefit from more aggressive primary prevention.

Background: Sharing of patient-level clinical trial data has been widely endorsed, yet little is known how extensively these have been utilized in cardiology. Methods: We extracted data from ClinicalStudyDataRequest.com (CSDR), a large, multi-sponsor, open access platform hosting patient-level data from completed studies sponsored by 13 pharmaceutical companies. Results: From January 2013 to May 2017, the platform had data from 3,374 clinical trials of which 537 (16%) were specific to cardiometabolic therapeutics (phase 1 36%; phase 2 17%; phase 2/3 1%; phase 3 42%; phase 4 4%). These covered 74 therapies and 398,925 patients ( Figure 1 ). Diabetes mellitus (60%) and hypertension (15%) were the most common study topics ( Figure 2 ). Median time from study completion to data availability was 79 months. As of March 2017, CSDR had received 305 submitted proposals, of which 154 had signed data sharing agreements. Thirty of these proposals were related to cardiometabolic therapies and requested data from 81 unique studies (90% of which were phase 3/4). Most proposals were from the US (53%) and half did not report a funding source. Most proposals focused on post hoc exploratory analyses, research methodology, or meta-analyses; only 2 re-analyzed the original study primary hypothesis. To date, 3 peer-reviewed papers have been published (median 19 months from the data sharing agreement). Conclusions: Although data from over 500 cardiometabolic trials have been made available on a large, multi-sponsor open access platform, only 15% of these trials have been accessed by investigators thus far and few findings have reached publication.

Introduction: Higher levels of high density lipoprotein cholesterol (HDL-C) are associated with reduced risk of cardiovascular disease (CVD). However, observational data suggest very high HDL-C may be associated with increased all-cause mortality. We aimed to investigate the relationship between HDL-C and CV mortality and morbidity. Methods: Using data from adults without prior CVD from 5 large U.S.-based cohorts available through NIH BioLINCC (Framingham Cohort Study, Framingham Offspring, Multi-ethnic Study of Atherosclerosis, Atherosclerosis Risk in Communities, and Cardiovascular Health Study), we assessed the association between HDL-C and all-cause death and CVD composite events (CV death, myocardial infarction, angina, or stroke) using Cox proportional hazards models, modeling HDL-C with restricted cubic splines to allow for non-linearity. Adjustment factors included age, race, systolic blood pressure, antihypertensive medications, diabetes, body-mass index, smoking status, low-density lipoprotein cholesterol, and weekly alcohol use. Results: Among 22,569 individuals (median age 56 years, 55% women), median (IQR) HDL-C was 50 mg/dL (41, 62). Those with HDL-C>50 mg/dL were more frequently female, non-smokers, and less obese. Over median follow up of 19.5 years, 6,539 deaths occurred (31% CV deaths). After adjustment for clinical factors, there was a U-shaped association between HDL-C and all-cause death in men, and to a lesser degree in women (Figure). As compared with a reference point of 50 mg/dL, lower HDL-C was associated with higher CVD composite events in both men and women, but higher HDL-C was not associated with increased CVD composite risk in either sex. Conclusions: In this large, U.S.-based study of well-characterized clinical cohorts and long-term follow-up, HDL-C displayed a U-shaped relationship with all-cause death. Low, but not high, HDL-C is associated with higher CVD composite events in both men and women.

We thank Dr Hayward for his interest in our article.1 First, we note that our study was not intended to negate a risk-based approach to statin therapy. In fact, some of us have pioneered and led multiple efforts in the development of risk prediction algorithms.2 Our finding that cumulative exposure to elevated non–high-density lipoprotein cholesterol increases coronary heart disease risk highlights that both cardiovascular disease risk and cardiovascular disease risk factor exposures should be considered over >10-year windows. In other words, duration of exposure to a risk factor, in this case hyperlipidemia, is important and should be used in part to identify those who may benefit from statin therapy and those who may be identified by current risk-based algorithms. Dr Hayward notes that our …

Introduction: The American Heart Association and American College of Cardiology (AHA/ACC) recently released updated guidelines for management of blood cholesterol, which differ from current European Society of Cardiology and European Atherosclerosis Society (ESC/EAS) guidelines. How these differences affect the overall number of individuals recommended for statin therapy in a country with high cardiovascular disease (CVD) risk remains unclear. Hypothesis: Due to the lower threshold for statin recommendations for primary prevention based on 10-year CVD risk under the AHA/ACC guidelines, more adults overall would be recommended for statin therapy under American compared to European guidelines. Methods: Using 2011 data from a nationwide cross-sectional survey in Poland (NATPOL), we estimated the number and characteristics of adults aged 40-65 recommended for lipid lowering therapy under the ESC/EAS and AHA/ACC guidelines. The survey sample of 1060 adults represented 13.5 million adults in Poland aged 40-65. Results: Under ESC/EAS guidelines, 47.6% of adults (44.6-50.7%) aged 40-65 were recommended for immediate statin therapy, compared to 49.9% (46.9-52.9%) under AHA/ACC guidelines. Among adults free of cardiovascular disease (CVD), 10.5% had discordant recommendations between guidelines. Individuals recommended for statin therapy under ACC/AHA but not ESC/EAS guidelines had less chronic kidney disease, higher HDL cholesterol, higher 10-year (AHA/ACC calculator) risk, and higher 30-year (Framingham) risk than adults recommended under ESC/EAS but not under ACC/AHA guidelines. Ten-year CVD mortality risk estimated by the SCORE algorithm was similar between the two groups. Conclusions: In spite of differences between current European and American cholesterol guidelines, when applied to a nationwide representative sample from a country with high CVD risk, the number of adults aged 40-65 recommended for cholesterol lowering therapy under each guideline was nearly identical. Although more adults met criteria for primary prevention based on 10-year CVD risk under new American guidelines, the impact of this is offset by additional criteria for statin therapy in current European guidelines.

BACKGROUND: Transesophageal echocardiography (TEE) is often recommended to exclude infective endocarditis (IE) in patients presenting with bacteremia despite a negative transthoracic echocardiogram (TTE). Previous studies showing inadequate sensitivity of TTE for native valve endocarditis are dated, and do not reflect modern advances in ultrasound image optimization technology. We hypothesized that with current generation echocardiography technology, a TTE absent mobile echo targets and without significant valvular abnormalities would have sufficient negative predictive value to exclude IE. METHODS: The Duke Echocardiographic Database was queried from 1/1/2007 [[Unable to Display Character: –]] 2/28/2014 for TTEs performed within 7 days prior to a TEE ordered for bacteremia/endocarditis. The dominant imaging platform used for both TTE and TEE during this era was the Philips IE33, with frequent use of fundamental frequencies to enhance spatial resolution beyond that of harmonic imaging alone. TTE studies identified as having poor sound transmission were excluded. A normal TTE was defined by the demonstration of normal cardiac anatomy, at most trivial valvular regurgitation, and absence of valvular stenosis, mobile/oscillating echo targets on valves, and hardware including catheters. The demonstration of an oscillating target on TEE along with clinical criteria based on chart review defined IE. RESULTS: A total of 974 unique patients had a TTE followed by a TEE within a week. IE was suggested in 209 of these patients by TEE. Among 107 patients meeting the a priori normal criteria on TTE, 3 patients had an abnormal TEE consistent with IE. These results correspond to a negative predictive value (NPV) of 97.2% (95% C.I. 91.4% - 99.3%) for a normal TTE to exclude IE. CONCLUSIONS: In this retrospective analysis from an academic medical center echocardiography laboratory, we demonstrated that an adequate quality TTE alone in a patient with a structurally normal heart without indwelling hardware has a high NPV for IE. Current TTE image optimization approaches may obviate the need to pursue TEE in patients after a recent preceding normal TTE.