External Control Arms in Idiopathic Pulmonary Fibrosis Using Clinical Trial and Real-World Data Sources.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which novel therapies are needed. External controls (ECs) could enhance IPF trial efficiency, but the direct comparability of ECs versus concurrent controls is unknown. Objectives: To develop IPF ECs by fit-for-purpose data standards to historical randomized clinical trial (RCT), multicenter registry (Pulmonary Fibrosis Foundation Patient Registry), and electronic health record (EHR) data and to evaluate endpoint comparability among ECs and the phase II RCT of BMS-986020. Methods: After data curation, the rate of change in FVC from baseline to 26 weeks among participants receiving BMS-986020 600 mg twice daily was compared with the BMS-placebo arm and ECs using mixed-effects models with inverse probability weights. Measurements and Main Results: At 26 weeks, the rates of change in FVC were -32.71 ml for BMS-986020 and -130.09 ml for BMS-placebo (difference, 97.4 ml; 95% confidence interval [CI], 24.6-170.2), replicating the original BMS-986020 RCT. RCT ECs showed treatment effect point estimates within the 95% CI of the original BMS-986020 RCT. Pulmonary Fibrosis Foundation Patient Registry ECs and EHR ECs experienced a slower rate of FVC decline compared with the BMS-placebo arm, resulting in treatment-effect point estimates outside of the 95% CI of the original BMS-986020 RCT. Conclusions: IPF ECs generated from historical RCT placebo arms result in comparable primary treatment effects to that of the original clinical trial, whereas ECs from real-world data sources, including registry or EHR data, do not. RCT ECs may serve as a potentially useful supplement to future IPF RCTs.

Heart Failure and Cognitive Impairment in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Previous studies suggest that heart failure (HF) is an independent risk factor for cognitive decline. A better understanding of the relationship between HF, cognitive status, and cognitive decline in a community-based sample may help clinicians understand disease risk. OBJECTIVE: To examine whether persons with HF have a higher prevalence of cognitive impairment and whether persons developing HF have more rapid cognitive decline. DESIGN: This observational cohort study of American adults in the Atherosclerosis Risk in Communities (ARIC) study has two components: cross-sectional analysis examining the association between prevalent HF and cognition using multinomial logistic regression, and change over time analysis detailing the association between incident HF and change in cognition over 15 years. PARTICIPANTS: Among visit 5 (2011-2013) participants (median age 75 years), 6495 had neurocognitive information available for cross-sectional analysis. Change over time analysis examined the 5414 participants who had cognitive scores and no prevalent HF at visit 4 (1996-1998). MEASUREMENTS: The primary outcome was cognitive status, classified as normal, mild cognitive impairment [MCI], and dementia on the basis of standardized cognitive tests (delayed word recall, word fluency, and digit symbol substitution). Cognitive change was examined over a 15-year period. Control variables included socio-demographic, vascular, and smoking/drinking measures. RESULTS: At visit 5, participants with HF had a higher prevalence of dementia (adjusted relative risk ratio [RRR] = 1.60 [95% CI 1.13, 2.25]) and MCI (RRR = 1.36 [1.12, 1.64]) than those without HF. A decline in cognition between visits 4 and 5 was - 0.07 standard deviation units [- 0.13, - 0.01] greater among persons who developed HF compared to those who did not. Results did not differ by ejection fraction. CONCLUSION: HF is associated with neurocognitive dysfunction and decline independent of other co-morbid conditions. Further study is needed to determine the underlying pathophysiology.

Associations Between Midlife Vascular Risk Factors and 25-Year Incident Dementia in the Atherosclerosis Risk in Communities (ARIC) Cohort.

Importance: Vascular risk factors have been associated with cognitive decline. Midlife exposure to these factors may be most important in conferring late-life risk of cognitive impairment. Objectives: To examine Atherosclerosis Risk in Communities (ARIC) participants in midlife and to explore associations between midlife vascular risk factors and 25-year dementia incidence. Design, Setting, and Participants: This prospective cohort investigation of the Atherosclerosis Risk in Communities (ARIC) Study was conducted from 1987-1989 through 2011-2013. The dates of this analysis were April 2015 through August 2016. The setting was ARIC field centers (Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis suburbs, Minnesota). The study comprised 15 744 participants (of whom 27.1% were black and 72.9% white) who were aged 44 to 66 years at baseline. Main Outcomes and Measures: Demographic and vascular risk factors were measured at baseline (obesity, smoking, diabetes, prehypertension, hypertension, and hypercholesterolemia) as well as presence of the APOE ε4 genotype. After the baseline visit, participants had 4 additional in-person visits, for a total of 5 in-person visits, hospitalization surveillance, telephone calls, and repeated cognitive evaluations. Most recently, in 2011-2013, through the ARIC Neurocognitive Study (ARIC-NCS), participants underwent a detailed neurocognitive battery, informant interviews, and adjudicated review to define dementia cases. Additional cases were identified through the Telephone Interview for Cognitive Status-Modified or informant interview, for participants not attending the ARIC-NCS visit, or by an International Classification of Diseases, Ninth Revision dementia code during a hospitalization. Fully adjusted Cox proportional hazards regression was used to evaluate associations of baseline vascular and demographic risk factors with dementia. Results: In total, 1516 cases of dementia (57.0% female and 34.9% black, with a mean [SD] age at visit 1 of 57.4 [5.2] years) were identified among 15 744 participants. Black race (hazard ratio [HR], 1.36; 95% CI, 1.21-1.54), older age (HR, 8.06; 95% CI, 6.69-9.72 for participants aged 60-66 years), lower educational attainment (HR, 1.61; 95% CI, 1.28-2.03 for less than a high school education), and APOE ε4 genotype (HR, 1.98; 95% CI, 1.78-2.21) were associated with increased risk of dementia, as were midlife smoking (HR, 1.41; 95% CI, 1.23-1.61), diabetes (HR, 1.77; 95% CI, 1.53-2.04), prehypertension (HR, 1.31; 95% CI, 1.14-1.51), and hypertension (HR, 1.39; 95% CI, 1.22-1.59). The HR for dementia for diabetes was almost as high as that for APOE ε4 genotype. Conclusions and Relevance: Midlife vascular risk factors are associated with increased risk of dementia in black and white ARIC Study participants. Further studies are needed to evaluate the mechanism of and opportunities for prevention of the cognitive sequelae of these risk factors in midlife.

Perceived discrimination and cancer screening behaviors in US Hispanics: the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study.

PURPOSE: Perceived discrimination has been associated with lower adherence to cancer screening guidelines. We examined whether perceived discrimination was associated with adherence to breast, cervical, colorectal, and prostate cancer screening guidelines in US Hispanic/Latino adults. METHODS: Data were obtained from the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study, including 5,313 Hispanic adults aged 18­74 from Bronx, NY, Chicago, IL, Miami, FL, and San Diego, CA, and those who were within appropriate age ranges for specific screening tests were included in the analysis. Cancer screening behaviors were assessed via self-report. Perceived discrimination was measured using the Perceived Ethnic Discrimination Questionnaire. Confounder-adjusted multivariable polytomous logistic regression models assessed the association between perceived discrimination and adherence to cancer screening guidelines. RESULTS: Among women eligible for screening, 72.1 % were adherent to cervical cancer screening guidelines and 71.3 %were adherent to breast cancer screening guidelines. In participants aged 50­74, 24.6 % of women and 27.0 % of men were adherent to fecal occult blood test guidelines; 43.5 % of women and 34.8 % of men were adherent to colonoscopy/sigmoidoscopy guidelines; 41.0 % of men were adherent to prostate-specific antigen screening guidelines. Health insurance coverage, rather than perceived ethnic discrimination,was the variable most associated with receiving breast, cervical,colorectal, or prostate cancer screening. CONCLUSIONS: The influence of discrimination as a barrier to cancer screening may be modest among Hispanics/Latinos in urban US regions. Having health insurance facilitates cancer screening in this population. Efforts to increase cancer screening in Hispanics/Latinos should focus on increasing access to these services, especially among the uninsured.

Pre-morbid body mass index and mortality after incident heart failure: the ARIC Study.

BACKGROUND: Although obesity is an independent risk factor for heart failure (HF), once HF is established, obesity is associated with lower mortality. It is unclear if the weight loss due to advanced HF leads to this paradoxical finding. OBJECTIVES: This study sought to evaluate the prognostic impact of pre-morbid obesity in patients with HF. METHODS: In the ARIC (Atherosclerosis Risk In Communities) study, we used body mass index (BMI) measured ≥6 months before incident HF (pre-morbid BMI) to evaluate the association of overweight (BMI 25 to <30 kg/m(2)) and obesity (BMI ≥30 kg/m(2)) compared with normal BMI (18.5 to <25 kg/m(2)) with mortality after incident HF. RESULTS: Among 1,487 patients with incident HF, 35% were overweight and 47% were obese by pre-morbid BMI measured 4.3 ± 3.1 years before HF diagnosis. Over 10-year follow-up after incident HF, 43% of patients died. After adjustment for demographics and comorbidities, being pre-morbidly overweight (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.58 to 0.90; p = 0.004) or obese (HR: 0.70; 95% CI: 0.56 to 0.87; p = 0.001) had a protective association with survival compared with normal BMI. The protective effect of overweight and obesity was consistent across subgroups on the basis of a history of cancer, smoking, and diabetes. CONCLUSIONS: Our results, for the first time, demonstrate that patients who were overweight or obese before HF development have lower mortality after HF diagnosis compared with normal BMI patients. Thus, weight loss due to advanced HF may not completely explain the protective effect of higher BMI in HF patients.

Trends in myocardial infarction rates and case fatality by anatomical location in four United States communities, 1987 to 2008 (from the Atherosclerosis Risk in Communities Study).

Although the incidence of and mortality after ST-segment elevation myocardial infarction (STEMI) is decreasing, time trends in anatomical location of STEMI and associated short-term prognosis have not been examined in a population-based community study. We determined 22-year trends in age- and race-adjusted gender-specific incidences and 28-day case fatality of hospitalized STEMI by anatomic infarct location among a stratified random sample of 35- to 74-year-old residents of 4 communities in the Atherosclerosis Risk in Communities study. STEMI infarct location was assessed by 12-lead electrocardiograms from the hospital record and was coded as anterior, inferior, lateral, and multilocation STEMIs using the Minnesota code. From 1987 to 2008, a total of 4,845 patients had an incident STEMI; 37.2% were inferior STEMI, 32.8% were anterior, 16.8% occurred in multiple infarct locations, and 13.2% were lateral STEMI. For inferior, anterior, and lateral STEMIs in both men and women, significant decreases were observed in the age-adjusted annual incidence and the associated 28-day case fatality. In contrast, for STEMI in multiple infarct locations, neither the annual incidence nor the 28-day case fatality changed over time. The age- and race-adjusted annual incidence and associated 28-day case fatality of STEMI in anterior, inferior, and lateral infarct locations decreased during 22 years of surveillance; however, no decrease was observed for STEMI in multiple infarct locations. In conclusion, our findings suggest that there is room for improvement in the care of patients with multilocation STEMI.

Design and rationale of a randomized trial comparing the Blalock-Taussig and right ventricle-pulmonary artery shunts in the Norwood procedure.

OBJECTIVE: The initial palliative procedure for patients born with hypoplastic left heart syndrome and related single right ventricle anomalies, the Norwood procedure, remains among the highest risk procedures in congenital heart surgery. The classic Norwood procedure provides pulmonary blood flow with a modified Blalock-Taussig shunt. Improved outcomes have been reported in a few small, nonrandomized studies of a modification of the Norwood procedure that uses a right ventricle-pulmonary artery shunt to provide pulmonary blood flow. Other nonrandomized studies have shown no differences between the two techniques. METHODS: The Pediatric Heart Network designed a randomized clinical trial to compare outcomes for subjects undergoing a Norwood procedure with either the right ventricle-pulmonary artery or modified Blalock-Taussig shunt. Infants with a diagnosis of single, morphologically right ventricle anomaly who are undergoing a Norwood procedure are eligible for inclusion in this study. The primary outcome is death or cardiac transplant 12 months after random assignment. Secondary outcomes include postoperative morbidity after Norwood and stage II palliation procedures, right ventricular function and pulmonary arterial growth at stage II palliation, and neurodevelopmental outcomes at 14 months old. Incidence of adverse events will also be compared between treatment groups. CONCLUSION: This study will make an important contribution to the care of patients with hypoplastic left heart syndrome and related forms of single, morphologically right ventricle. It also establishes a model with which other operative interventions for patients with congenital cardiovascular malformations can be evaluated in the future.

Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome.

BACKGROUND: Cardiovascular disease, including aortic root dilation, dissection, and rupture, is the leading cause of mortality in patients with Marfan syndrome (MFS). The maximal aortic root diameter at the sinuses of Valsalva is considered the best predictor of adverse cardiovascular outcome. Although advances in therapy have improved life expectancy, affected individuals continue to suffer cardiovascular morbidity and mortality. Recent studies in an FBN1-targeted mouse model of MFS with aortic disease similar to that seen in humans showed that treatment with losartan normalized aortic root growth and aortic wall architecture. METHODS: The Pediatric Heart Network designed a randomized clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in subjects with MFS receiving atenolol or losartan. Individuals 6 months to 25 years of age with a body surface area-adjusted aortic root z score >3.0 will be eligible for inclusion. The primary aim is to compare the effect of atenolol therapy with that of losartan therapy on the rate of aortic root growth over 3 years. Secondary end points include progression of aortic regurgitation; incidence of aortic dissection, aortic root surgery, and death; progression of mitral regurgitation; left ventricular size and function; echocardiographically derived measures of central aortic stiffness; skeletal and somatic growth; and incidence of adverse drug reactions. CONCLUSION: This randomized trial should make a substantial contribution to the management of individuals with MFS and expand our understanding of the mechanisms responsible for the aortic manifestations of this disorder.