Evaluation of Direct Oral Anticoagulant Reversal Agents in Intracranial Hemorrhage: A Systematic Review and Meta-analysis.

Importance: Direct oral anticoagulant (DOAC)-associated intracranial hemorrhage (ICH) has high morbidity and mortality. The safety and outcome data of DOAC reversal agents in ICH are limited. Objective: To evaluate the safety and outcomes of DOAC reversal agents among patients with ICH. Data Sources: PubMed, MEDLINE, The Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL databases were searched from inception through April 29, 2022. Study Selection: The eligibility criteria were (1) adult patients (age ≥18 years) with ICH receiving treatment with a DOAC, (2) reversal of DOAC, and (3) reported safety and anticoagulation reversal outcomes. All nonhuman studies and case reports, studies evaluating patients with ischemic stroke requiring anticoagulation reversal or different dosing regimens of DOAC reversal agents, and mixed study groups with DOAC and warfarin were excluded. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for abstracting data and assessing data quality and validity. Two reviewers independently selected the studies and abstracted data. Data were pooled using the random-effects model. Main Outcomes and Measures: The primary outcome was proportion with anticoagulation reversed. The primary safety end points were all-cause mortality and thromboembolic events after the reversal agent. Results: A total of 36 studies met criteria for inclusion, with a total of 1832 patients (967 receiving 4-factor prothrombin complex concentrate [4F-PCC]; 525, andexanet alfa [AA]; 340, idarucizumab). The mean age was 76 (range, 68-83) years, and 57% were men. For 4F-PCC, anticoagulation reversal was 77% (95% CI, 72%-82%; I2 = 55%); all-cause mortality, 26% (95% CI, 20%-32%; I2 = 68%), and thromboembolic events, 8% (95% CI, 5%-12%; I2 = 41%). For AA, anticoagulation reversal was 75% (95% CI, 67%-81%; I2 = 48%); all-cause mortality, 24% (95% CI, 16%-34%; I2 = 73%), and thromboembolic events, 14% (95% CI, 10%-19%; I2 = 16%). Idarucizumab for reversal of dabigatran had an anticoagulation reversal rate of 82% (95% CI, 55%-95%; I2 = 41%), all-cause mortality, 11% (95% CI, 8%-15%, I2 = 0%), and thromboembolic events, 5% (95% CI, 3%-8%; I2 = 0%). A direct retrospective comparison of 4F-PCC and AA showed no differences in anticoagulation reversal, proportional mortality, or thromboembolic events. Conclusions and Relevance: In the absence of randomized clinical comparison trials, the overall anticoagulation reversal, mortality, and thromboembolic event rates in this systematic review and meta-analysis appeared similar among available DOAC reversal agents for managing ICH. Cost, institutional formulary status, and availability may restrict reversal agent choice, particularly in small community hospitals.

Endothelial Dysfunction and Racial Disparities in Mortality and Adverse Cardiovascular Disease Outcomes.

BACKGROUND: The contribution of arterial endothelial dysfunction (ED) to increased cardiovascular disease (CVD) risk among Blacks is not known. HYPOTHESIS: We investigated whether peripheral arterial ED explains racial disparity in CVD events. METHODS: Data from the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study was used. Endothelial dysfunction was assessed by the Framingham reactive hyperemia index (fRHI), measured using pulse amplitude tonometry (PAT). Lower values of fRHI indicate more severe ED. The primary outcome of interest was combined CVD events and all-cause mortality. RESULTS: 1454 individuals (62% female, 40% Black, mean age 59 ± 8 years) had available data on fRHI (mean [SD]: 0.74 [0.46]). Over a mean follow-up period of 8.0 ± 2.4 years (11,186 person-years), 116 events were observed. Black race, male sex, smoking, diabetes, blood pressure, triglycerides, C-reactive protein, and interleukin-6 were inversely correlated with fRHI in univariate models. In an unadjusted Cox regression model, fRHI was associated with 20% lower risk of the primary outcome events (hazard ratio [HR] per 1-SD higher fRHI: 0.80, 95% confidence interval [CI]: 0.66-0.97). However, this association was no longer significant after adjustment for CVD risk factors (HR: 0.90, 95% CI: 0.74-1.11). In an age- and sex-adjusted model, Blacks had 1.68 (95% CI: 1.16-2.43) higher risk of primary outcome compared with Whites. This association was not significantly attenuated by addition of fRHI to the multivariable models. CONCLUSION: Black race is associated with increased risk of CVD events and mortality independent of its associations with ED, as measured by PAT.

Assessing Longitudinal Invariance of the Center for Epidemiologic Studies-Depression Scale Among Middle-Aged and Older Adults.

BACKGROUND AND PURPOSE: The longitudinal invariance of the Center for Epidemiologic Studies-Depression (CES-D) scale among middle-aged and older adults is unknown. This study examined the factorial invariance of the CES-D scale in a large cohort of community-based adults longitudinally. METHODS: 1,204 participants completed the 20-item CES-D scale at 4 time points 1 year apart. Structural equation modeling was used to identify best fitting model using longitudinal data at baseline and at 1-, 2-, and 3-year follow-up. RESULTS: The 4-factor model showed partial invariance over 3 years. Two of the 6 noninvariant items were consistently noninvariant at the 3 follow-up points. CONCLUSION: Special consideration should be given to these 2 items when using the CES-D scale in healthy adults (45-75 years old).

Relation of obstructive sleep apnea to coronary artery calcium in non-obese versus obese men and women aged 45-75 years.

Sleep apnea and obesity are strongly associated, and both increase the risk for coronary artery disease. Several cross-sectional studies have reported discrepant results regarding the role obesity plays in the relation between sleep apnea and coronary artery calcium (CAC), a marker of subclinical coronary disease. The aim of the present study was to investigate the association between sleep apnea and the presence of CAC in a community cohort of middle-aged men and women without preexisting cardiovascular disease, stratified by body mass index (<30 vs ≥30 kg/m(2)). Participants underwent electron-beam computed tomography to measure CAC and underwent home sleep testing for sleep apnea. The presence of CAC was defined as an Agatston score >0. Sleep apnea was analyzed categorically using the apnea-hypopnea index. The sample was composed of primarily men (61%) and Caucasians (56%), with a mean age of 61 years. The prevalence of CAC was 76%. In participants with body mass indexes <30 kg/m(2) (n = 139), apnea-hypopnea index ≥15 (vs <5) was associated with 2.7-fold odds of having CAC, but the effect only approached significance. Conversely, in participants with body mass indexes ≥30 kg/m(2), sleep apnea was not independently associated with CAC. In conclusion, sleep apnea is independently associated with early atherosclerotic plaque burden in nonobese patients.

Traditional and nontraditional cardiovascular risk factors in comorbid insomnia and sleep apnea.

OBJECTIVES: Insomnia and sleep apnea frequently co-occur and are independently associated with an increased risk of cardiovascular disease, but little is known about cardiovascular disease risk among individuals with comorbid insomnia and sleep apnea. The current study examined traditional risk factors and a physiologic biomarker of cardiovascular risk in comorbid insomnia and sleep apnea. DESIGN: Community-based participatory research study. PARTICIPANTS: The sample comprised 795 participants without preexisting cardiovascular disease from the Heart Strategies Concentrating On Risk Evaluation (Heart SCORE) study. MEASUREMENTS AND RESULTS: Participants were assessed for symptoms of insomnia and sleep apnea risk, as well as for presence of obesity, smoking, a sedentary lifestyle, hypertension, dyslipidemia, and diabetes. Baseline resting brachial artery diameter was measured by B-mode ultrasonography. A total of 138 participants (17.4%) met criteria for insomnia syndrome alone, 179 (22.5%) were at high risk for sleep apnea alone, 95 (11.9%) reported both insomnia syndrome and high sleep apnea risk, and 383 (48.2%) reported having neither insomnia nor sleep apnea symptoms Both high sleep apnea risk alone and comorbid insomnia and high sleep apnea risk groups had greater frequencies of obesity, sedentary lifestyle, hypertension, and three or more traditional cardiovascular risk factors and significantly larger brachial artery diameters than the insomnia alone group and those without insomnia or sleep apnea symptoms. No differences in traditional cardiovascular risk factors or brachial artery diameter were found between the high sleep apnea risk and comorbid groups. CONCLUSIONS: These findings suggest that sleep apnea is a major contributor to cardiovascular risk and co-occurring insomnia does not appear to add to this risk.

Relationship among low cholesterol levels, depressive symptoms, aggression, hostility, and cynicism.

BACKGROUND: Treatment guidelines for lipids have become increasingly more aggressive. However, naturally low or therapeutically reduced cholesterol levels may be associated with adverse psychological health symptoms, including depression, aggression, and hostility. OBJECTIVE: To examine relationships between low total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol levels and measures of psychosocial status among middle-aged adults. METHODS: A total of 1995 subjects enrolled in the Heart Strategies Concentrating on Risk Evaluation study with data on TC, LDL cholesterol, and self-reported ratings of psychological health were evaluated. To quantify ratings of depression, aggression, cynicism, and hostility, psychological measures included the Center for Epidemiologic Studies Depression Scale (CES-D) and Cook-Medley Hostility Inventory. RESULTS: Of 1995 participants, 25.1% were taking a lipid-lowering agent at baseline. Mean CES-D scores were similar between participants with low (<150 mg/dL) versus greater (≥150 mg/dL) TC and low (<100 mg/dL) versus higher (≥100 mg/dL) LDL cholesterol. However, among 22 participants with LDL cholesterol <70 mg/dL, the prevalence of clinically significant depressive symptomatology (CES-D score ≥16) was 31.8% compared with 12.1% in the remaining cohort (P = .005). In multivariable analysis, low LDL cholesterol (<100 mg/dL) was associated with cynicism (partial r = -0.14, P = .02) and hostility (partial r = -0.18, P = .004), but only in the subgroup of white subjects currently taking lipid-lowering medications. Low LDL cholesterol (versus non-low) was associated with greater aggression scores but only among participants currently taking psychiatric medications (3.4 ± 1.7 vs 2.8 ± 1.5, P = .02). CONCLUSIONS: Our data indicate mixed evidence for independent relationships between low total and LDL cholesterol levels and impaired psychological health.

Sociodemographic, clinical, and psychological factors associated with attrition in a prospective study of cardiovascular prevention: the Heart Strategies Concentrating on Risk Evaluation study.

PURPOSE: To identify factors associated with attrition in a longitudinal study of cardiovascular prevention. METHODS: Demographic, clinical, and psychosocial variables potentially associated with attrition were investigated in 1841 subjects enrolled in the southwestern Pennsylvania Heart Strategies Concentrating on Risk Evaluation study. Attrition was defined as study withdrawal, loss to follow-up, or missing 50% or more of study visits. RESULTS: Over 4 years of follow-up, 291 subjects (15.8%) met criteria for attrition. In multivariable regression models, factors that were independently associated with attrition were black race (odds ratio [OR], 2.21; 95% confidence interval [CI], 1.55-3.16; P < .001), younger age (OR per 5-year increment, 0.88; 95% CI, 0.79-0.99; P < .05), male gender (OR, 1.79; 95% CI, 1.27-2.54; P < .05), no health insurance (OR, 2.04; 95% CI, 1.20-3.47; P < .05), obesity (OR, 1.80; 95% CI, 1.07-3.02; P < .05), CES-D depression score 16 or higher (OR, 2.02; 95% CI, 1.29-3.19; P < .05), and higher ongoing life events questionnaire score (OR, 1.09; 95% CI, 1.04-1.13; P < .001). Having a spouse/partner participating in the study was associated with lower odds of attrition (OR, 0.60; 95% CI, 0.37-0.97; P < .05). A synergistic interaction was identified between black race and depression. CONCLUSIONS: Attrition over 4 years was influenced by sociodemographic, clinical, and psychological factors that can be readily identified at study entry. Recruitment and retention strategies targeting these factors may improve participant follow-up in longitudinal cardiovascular prevention studies.

Biogeographic ancestry, self-identified race, and admixture-phenotype associations in the Heart SCORE Study.

Large epidemiologic studies examining differences in cardiovascular disease (CVD) risk factor profiles between European Americans and African Americans have exclusively used self-identified race (SIR) to classify individuals. Recent genetic epidemiology studies of some CVD risk factors have suggested that biogeographic ancestry (BGA) may be a better predictor of CVD risk than SIR. This hypothesis was investigated in 464 African Americans and 771 European Americans enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) Study in March and April 2010. Individual West African and European BGA were ascertained by means of a panel of 1,595 genetic ancestry informative markers. Individual BGA varied significantly among African Americans and to a lesser extent among European Americans. In the total cohort, BGA was not found to be a better predictor of CVD risk factors than SIR. Both measures predicted differences in the presence of the metabolic syndrome, waist circumference, triglycerides, body mass index, very low density lipoprotein cholesterol, lipoprotein A, and systolic and diastolic blood pressure between European Americans and African Americans. These results suggest that for most nongenetic cardiovascular epidemiology studies, SIR is sufficient for predicting CVD risk factor differences between European Americans and African Americans. However, higher body mass index and diastolic blood pressure were significantly associated with West African BGA among African Americans, suggesting that BGA should be considered in genetic cardiovascular epidemiology studies carried out among African Americans.

Low prevalence of "ideal cardiovascular health" in a community-based population: the heart strategies concentrating on risk evaluation (Heart SCORE) study.

BACKGROUND: Cardiovascular health is a new construct defined by the American Heart Association (AHA) as part of its 2020 Impact Goal definition. The applicability of this construct to community-based populations and the distributions of its components by race and sex have not been reported. METHODS AND RESULTS: The AHA construct of cardiovascular health and the AHA ideal health behaviors index and ideal health factors index were evaluated among 1933 participants (mean age 59 years; 44% blacks; 66% women) in the community-based Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study. One of 1933 participants (0.1%) met all 7 components of the AHA's definition of ideal cardiovascular health. Less than 10% of participants met ≥ 5 components of ideal cardiovascular health in all subgroups (by race, sex, age, and income level). Thirty-nine subjects (2.0%) had all 4 components of the ideal health behaviors index and 27 (1.4%) had all 3 components of the ideal health factors index. Blacks had significantly fewer ideal cardiovascular health components than whites (2.0 ± 1.2 versus 2.6 ± 1.4; P < 0.001). After adjustment by sex, age, and income level, blacks had 82% lower odds of having ≥ 5 components of ideal cardiovascular health (odds ratio 0.18, 95% confidence interval, 0.10 to 0.34; P<0.001). No interaction was found between race and sex. CONCLUSION: The prevalence of ideal cardiovascular health is extremely low in a middle-aged community-based study population. Comprehensive individual and population-based interventions must be developed to support the attainment of the AHA's 2020 Impact Goal for cardiovascular health.

Predictors of significant short-term increases in blood pressure in a community-based population.

BACKGROUND: Blood pressure predicts the risk of cardiovascular disease events in a linear, graded manner. Factors associated with significant short-term increases in blood pressure are not well established. We aimed to identify predictors of a significant increase in blood pressure over a 1-year period among nonhypertensive, community-dwelling adults. METHODS: From the community-based Heart Strategies Concentrating on Risk Evaluation study, 509 nonhypertensive adults (mean age 58 years; 68% were female; 24% were black) had baseline and 1-year assessments of blood pressure. Demographics, medical history, anthropometrics, lipids/lipoproteins, physical activity, and psychologic status were measured at both intervals. A "significant" increase in blood pressure was defined as an increase in systolic blood pressure of greater than 20 mm Hg, diastolic blood pressure of greater than 10 mm Hg, or initiation of antihypertensive medication. RESULTS: At 1 year, 22% of participants had a significant increase in blood pressure. In multivariable analysis, baseline body mass index (BMI) and a greater than 5% increase in weight or waist circumference were associated with a significant increase in blood pressure (adjusted relative risk 2.09; 95% confidence interval, 1.35-3.21). The adverse effect of an increase in weight and waist circumference on blood pressure was evident in subgroup analyses by age, race, baseline BMI, and regular exercise. CONCLUSIONS: Baseline BMI and a greater than 5% increase in weight or waist circumference over 1 year are associated with a significant increase in blood pressure. These data emphasize the need for weight maintenance. They also serve to stratify individuals who may benefit from close clinical observation and preventive intervention.

Racial differences in coronary artery calcification are not attributed to differences in lipoprotein particle sizes: the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) Study.

BACKGROUND: Lipoprotein particle levels and size distributions differ by race. As a group, blacks have less coronary artery calcification (CAC) than whites. We evaluated whether racial differences in CAC are explained by differences in lipoprotein levels and particle sizes. METHODS: A total of 721 blacks and 988 whites underwent measurement of fasting lipoprotein levels and particle sizes. There were 608 subjects who had CAC quantified by electron beam computed tomography. Distributions and interrelationships among lipoprotein levels, particle sizes, and CAC were evaluated by race and sex. RESULTS: Blacks had nominally higher adjusted high-density lipoprotein cholesterol levels (men, 51 vs 50 mg/dL; women, 63 vs 61 mg/dL; P = .05), lower intermediate-density lipoprotein cholesterol levels (women only, 17 vs 18 mg/dL; P = .02), and significantly lower triglyceride levels (men, 116 vs 138 mg/dL; women, 103 vs 136 mg/dL; P < .0001) than whites. Adjusted small dense low-density lipoprotein 3 particle levels were significantly lower (P < .0001) in black men (47 vs 53 mg/dL) and black women (43 vs 48 mg/dL) compared with white men and women, respectively. Black race was associated with a 48% lower adjusted odds of moderate or significant CAC (odds ratio, 0.52; 95% confidence interval, 0.34-0.80). However, this strong association between race and CAC was independent of lipoprotein levels and particle sizes. CONCLUSIONS: Blacks have less CAC and more favorable lipoprotein profiles than whites. Racial differences in CAC are not attributable to differences in lipoprotein particle sizes. Future studies of mechanisms of race-related differences in CAC may enhance understanding of the pathophysiology of racial differences in cardiovascular disease.