The Testosterone Trials: Seven coordinated trials of testosterone treatment in elderly men.

Background The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results. Purpose To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and to determine definitively whether testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions. Methods We present the scientific and clinical rationale for the decisions made in the design of this set of trials. Results We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, common approaches to treatment and monitoring, and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data and safety monitoring board, the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in participant selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary outcomes for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation. Potential limitations Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one participant. Conclusion Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort.

Prevalence, prospective risk markers, and prognosis associated with the presence of left ventricular diastolic dysfunction in young adults: the coronary artery risk development in young adults study.

The authors sought to determine the prevalence, prospective risk markers, and prognosis associated with diastolic dysfunction in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The CARDIA Study cohort includes approximately equal proportions of white and black men and women. The authors collected data on risk markers at year 0 (1985-1986), and echocardiography was done at year 5 when the participants were 23-35 years of age. Participants were followed for 20 years (through 2010) for a composite endpoint of all-cause mortality, myocardial infarction, heart failure, and stroke. Diastolic function was defined according to a validated hierarchical classification algorithm. In the 2,952 participants included in the primary analysis, severe diastolic dysfunction was present in 1.1% and abnormal relaxation was present in 9.3%. Systolic blood pressure at year 0 was associated with both severe diastolic dysfunction and abnormal relaxation 5 years later, whereas exercise capacity and pulmonary function abnormalities were associated only with abnormal relaxation 5 years later. After multivariate adjustment, the hazard ratios for the composite endpoint in participants with severe diastolic dysfunction and abnormal relaxation were 4.3 (95% confidence interval: 2.0, 9.3) and 1.6 (95% confidence interval: 1.1, 2.5), respectively. Diastolic dysfunction in young adults is associated with increased morbidity and mortality, and the identification of prospective risk markers associated with diastolic dysfunction could allow for targeted primary prevention efforts.

Differences in specialist consultations for cardiovascular disease by race, ethnicity, gender, insurance status, and site of primary care.

BACKGROUND: Consultation with cardiologists may improve the quality of ambulatory care and reduce disparities for patients with heart disease. We assessed the use of cardiology consultations and the associated quality by race/ethnicity, gender, insurance status, and site of care. METHODS AND RESULTS: In a retrospective cohort, we examined electronic records of 9761 adults with coronary artery disease or congestive heart failure (CHF) receiving primary care at practices affiliated with 2 academic medical centers during 2000 to 2005. During this period, 79.6% of patients with coronary artery disease and 90.3% of patients with CHF had a cardiology consultation. In multivariate analyses, women were less likely to receive a consultation than men for both conditions (coronary artery disease: hazard ratio, 0.89; 95% CI, 0.85 to 0.93; CHF: hazard ratio, 0.93; 95% CI, 0.87 to 0.99). Women also had 15% fewer follow-up consultations than men (P<0.001). Similarly, patients at community health centers were less likely to receive a consultation (coronary artery disease: hazard ratio, 0.79; 95% CI, 0.74 to 0.84; CHF: hazard ratio, 0.77; 95% CI: 0.71 to 0.84) and had 20% fewer follow-up consultations (P<0.001) relative to those at hospital-based practices. Black and Hispanic patients with CHF had 13% fewer follow-up consultations than white patients (P=0.01 and P=0.04, respectively). In adjusted analyses, consultation was associated with better processes of care compared with no consultation (P<0.001), particularly for women (P<0.001 for interaction between consultation and gender). CONCLUSIONS: Among ambulatory patients with coronary artery disease or CHF, women and those at community health centers have less access to cardiologists. Consultation is associated with better quality of care and narrows the gender gap in quality.

Addressing disparities in sudden cardiac arrest care and the underutilization of effective therapies.

Sudden cardiac arrest (SCA) is the most common cause of death in the Unites States. Despite its major impact on public health, significant challenges exist at the patient, provider, public, and policy levels with respect to raising more widespread awareness and understanding of SCA risks, identifying patients at risk for SCA, addressing barriers to SCA care, and eliminating disparities in SCA care and outcomes. To address many of these challenges, the Duke Center for the Prevention of Sudden Cardiac Death at the Duke Clinical Research Institute (Durham, NC) held a think tank meeting on December 7, 2009, convening experts on this issue from clinical cardiology, cardiac electrophysiology, health policy and economics, the US Food and Drug Administration, the Centers for Medicare and Medicaid Services, the Agency for Health Care Research and Quality, and device and pharmaceutical manufacturers. The specific goals of the meeting were to examine existing educational tools on SCA for patients, health care providers, and the public and explore ways to enhance and disseminate these tools; to propose a framework for improved identification of patients at risk of SCA; and to review the latest data on disparities in SCA care and explore ways to reduce these disparities. This article summarizes the discussions that occurred at the meeting.

Eliminating the Sex and Gender Gap and Transforming the Cardiovascular Health of All Women.

Critical to eliminating the sex and gender gap in cardiovascular health is addressing known differences in disease burden, disparities in treatment and clinical outcomes, and the scientific importance of sex as a biological variable that influences resilience, pathophysiology, and ultimately the health of women. Furthermore, key disparities exist at the intersection of sex/gender and race/ethnicity where women of color are disproportionately affected by higher burden of disease and poorer outcomes in several cardiovascular conditions. Through efforts to galvanize strategic partnerships, The NHLBI Strategic Vision sets forth research priorities across all of its objectives relevant to the cardiovascular health of women; it encourages strategic partnerships in both establishing and implementing research priorities. The Vision promotes a promise of precision medicine that embraces sex as its highest order, leverages an integrated approach to data science, explores sex influences on molecular underpinnings of disease, and advances sex-specific and race-sex interaction analyses toward the elimination of gaps in the cardiovascular care and health of all women.

Race-ethnic and sex differences in left ventricular structure and function: the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

BACKGROUND: We investigated race-ethnic and sex-specific relationships of left ventricular (LV) structure and LV function in African American and white men and women at 43 to 55 years of age. METHODS AND RESULTS: The Coronary Artery Risk Development in Young Adults (CARDIA) Study enrolled African American and white adults, age 18 to 30 years, from 4 US field centers in 1985-1986 (Year-0) who have been followed prospectively. We included participants with echocardiographic assessment at the Year-25 examination (n=3320; 44% men, 46% African American). The end points of LV structure and function were assessed using conventional echocardiography and speckle-tracking echocardiography. In the multivariable models, we used, in addition to race-ethnic and gender terms, demographic (age, physical activity, and educational level) and cardiovascular risk variables (body mass index, systolic blood pressure, diastolic blood pressure, heart rate, presence of diabetes, use of antihypertensive medications, number of cigarettes/day) at Year-0 and -25 examinations as independent predictors of echocardiographic outcomes at the Year-25 examination (LV end-diastolic volume [LVEDV]/height, LV end-systolic volume [LVESV]/height, LV mass [LVM]/height, and LVM/LVEDV ratio for LV structural indices; LV ejection fraction [LVEF], Ell, and Ecc for systolic indices; and early diastolic and atrial ratio, mitral annulus early peak velocity, ratio of mitral early peak velocity/mitral annulus early peak velocity; ratio, left atrial volume/height, longitudinal peak early diastolic strain rate, and circumferential peak early diastolic strain rate for diastolic indices). Compared with women, African American and white men had greater LV volume and LV mass (P<0.05). For LV systolic function, African American men had the lowest LVEF as well as longitudinal (Ell) and circumferential (Ecc) strain indices among the 4 sex/race-ethnic groups (P<0.05). For LV diastolic function, African American men and women had larger left atrial volumes; African American men had the lowest values of Ell and Ecc for diastolic strain rate (P<0.05). These race/sex differences in LV structure and LV function persisted after adjustment. CONCLUSIONS: African American men have greater LV size and lower LV systolic and diastolic function compared to African American women and to white men and women. The reasons for these racial-ethnic differences are partially but not completely explained by established cardiovascular risk factors.

Centers for cardiovascular outcomes research: defining a collaborative vision.

BACKGROUND: Recognizing the value of outcomes research to understand and bridge translational gaps, to establish evidence in clinical practice and delivery of medicine, and to generate new hypotheses on ongoing questions of treatment and care, the National Heart, Lung, and Blood Institute of the National Institutes of Health established the Centers for Cardiovascular Outcomes Research program in 2010. METHODS AND RESULTS: The National Heart, Lung, and Blood Institute funded 3 centers and a research coordinating unit. Each center has an independent project focus, including (1) characterizing care transition and predicting clinical events and quality of life for patients discharged after an acute coronary syndrome; (2) identifying center and regional factors associated with better patient outcomes across several cardiovascular conditions and procedures; and (3) examining the impact of healthcare reform in Massachusetts on overall and disparate care and outcomes for several cardiovascular conditions and venous thromboembolism. Cross-program collaborations seek to advance the field methodologically and to develop early-stage investigators committed to careers in outcomes research. CONCLUSIONS: The Centers for Cardiovascular Outcomes Research program represents a significant investment in cardiovascular outcomes research by the National Heart, Lung, and Blood Institute. The vision of this program is to leverage scientific rigor and cross-program collaboration to advance the science of healthcare delivery and outcomes beyond what any individual unit could achieve alone.

Longitudinal determinants of left ventricular mass and geometry: the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

BACKGROUND: The purpose of this study was to identify determinants of 20-year change in left ventricular (LV) mass (LVM) and LV geometry in black and white young adults in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. METHODS AND RESULTS: We studied 2426 black and white men and women (54.7% white) aged 43 to 55 years with cardiovascular risk factor data and echocardiograms from CARDIA year 5 and 25 examinations. In regression models, year 25 LVM or relative wall thickness was the dependent variable and with year 5 echo values, age, sex, race, body mass index, change in body mass index, mean arterial blood pressure, change in mean blood pressure, heart rate, change in heart rate, tobacco use, presence of diabetes mellitus, alcohol use, and physical activity score as independent variables. LVM and relative wall thickness increased, whereas prevalence of normal geometry declined from 84.2% to 69.7%. Significant determinants of year 25 LVM/m(2.7) were year 5 LVM, year 5 and change in body mass index, year 5 and change in mean arterial pressure, year 5 and change in heart rate, baseline diabetes mellitus, and year 5 tobacco and alcohol use (overall r(2)=0.40). Significant determinants of year 25 relative LV wall thickness were year 5 value, black race, change in body mass index, year 5 and change in mean arterial pressure, starting smoking, and year 5 diabetes mellitus (overall r(2)=0.11). CONCLUSIONS: Prevalence of abnormal LV hypertrophy and geometry increased from young adulthood to middle age. Both young adult cardiovascular risk traits and change in these traits predicted change in LV mass/geometry.