Matthew J. Budoff

THE TESTOSTERONE TRIALS: THE DESIGN OF SEVEN COORDINATED TRIALS TO DETERMINE IF TESTOSTERONE TREATMENT BENEFITS 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.

DEGREE OF LEFT VENTRICULAR SYSTOLIC DYSFUNCTION BY CARDIAC COMPUTED TOMOGRAPHIC ANGIOGRAPHY IMPROVES RISK STRATIFICATION AND DISCRIMINATION OF PATIENTS AT RISK FOR INCIDENT MORTALITY: RESULTS FROM 7907 PATIENTS IN THE PROSPECTIVE MULTICENTER INTERNATIONAL CONFIRM STUDY

Prior studies have evaluated the prognostic utility of left ventricular systolic dysfunction (LVSD) by cardiac CT angiography (CCTA), but have been limited to measures of normal versus abnormal function. Whether the degree of LVSD improves risk stratification and discrimination for mortality

LONG-TERM CARDIOVASCULAR OUTCOMES IN PATIENTS WITH ANOMALOUS CORONARY ARTERIES WISUALIZED BY CORONARY CT ANGIOGRAPHY: THE CONFIRM (CORONARY CT ANGIOGRAPHY EVALUATION FOR CLINICAL OUTCOMES: AN INTERNATIONAL MULTICENTER) REGISTRY

Background: Anomalous origin of coronary arteries (ACA) in young adults are thought to confer high mortality risk, but the clinical significance of incidentally discovered anomalous coronaries in middle-aged adults is not well characterized. We examined the clinical characteristics and 5-year

LONG-TERM MORTALITY BENEFIT OF EARLY CORONARY REVASCULARIZATION VERSUS MEDICAL THERAPY IN PATIENTS WITHOUT KNOWN CORONARY ARTERY DISEASE UNDERGOING CORONARY COMPUTED TOMOGRAPHIC ANGIOGRAPHY: RESULTS FROM CONFIRM REGISTRY

The long-term survival benefit of early revascularization for high-risk coronary artery disease (CAD) detected by coronary computed tomographic angiography (CCTA) is unknown. We examined 5544 stable angina patients (mean age 60±12, 63% male) without known CAD undergoing CCTA who were followed for

LONG-TERM PROGNOSTIC VALUE OF CORONARY COMPUTED TOMOGRAPHIC ANGIOGRAPHY FINDINGS FOR ASYMPTOMATIC INDIVIDUALS: A 6-YEAR FOLLOW-UP OF 1,226 ASYMPTOMATIC INDIVIDUALS FROM THE PROSPECTIVE MULTICENTER INTERNATIONAL CONFIRM STUDY

The long-term prognostic benefit of coronary computed tomographic angiography (CCTA) findings of coronary artery disease (CAD) in asymptomatic population is unknown. From the prospective multicenter international CONFIRM long-term study (N=17,181), we evaluated asymptomatic subjects without known

PROGNOSTIC UTILITY OF CORONARY ATHEROSCLEROSIS IN THE ABSENCE OF STENOSIS: A PROSPECTIVE MULTICENTER INTERNATIONAL STUDY OF 6,656 PATIENTS UNDERGOING CORONARY COMPUTED TOMOGRAPHIC ANGIOGRAPHY

Coronary atherosclerosis can exist in the absence of concurrent stenosis due to positive arterial remodeling, but whether these lesions are related to future adverse prognosis is unknown. We explored the prevalence and prognosis for stable patients who exhibited atherosclerotic plaque without

The Relationship of Coronary Artery Calcium To Coronary Heart Disease Events is Similar in Young and Elderly Participants in The Multi-Ethnic Study of Atherosclerosis: A Secondary Analysis of a Prospective Population-based Cohort

OBJECTIVE To evaluate the association of coronary artery calcium (CAC) and coronary heart disease (CHD) events among young and elderly individuals. PARTICIPANTS AND METHODS This is a secondary analysis of data from a prospective, multiethnic, population-based cohort study designed to study subclinical atherosclerosis. A total of 6809 persons 45 through 84 years old without known cardiovascular disease at baseline were enrolled from July 2000 through September 2002. All participants had CAC scoring performed and were followed up for a median of 8.5 years. The main outcome measures studied were CHD events, defined as myocardial infarction, definite angina or probable angina followed by revascularization, resuscitated cardiac arrest, or death attributable to CHD. RESULTS Comparing individuals with a CAC score of 0 with those with a CAC score greater than 100, there was an increased incidence of CHD events from 1 to 21 per 1000 person-years and 2 to 23 per 1000 person-years in the 45- through 54-year-old and 75- through 84-year-old groups, respectively. Compared with a CAC score of 0, CAC scores of 1 through 100 and greater than 100 impart an increased multivariable-adjusted CHD event risk in the 45- through 54-year-old and 75- through 84-year-old groups (hazard ratio [HR], 2.3; 95% CI, 0.9-5.8; for those 45-54 years old with CAC scores of 1-100; HR, 12.4; 95% CI, 5.1-30.0; for those 45-54 years old with CAC scores >100: HR, 5.4; 95% CI, 1.2-23.8; for those 75-84 years old with CAC scores of 1-100; and HR, 12.1; 95% CI, 2.9-50.2; for those 75-84 years old with CAC scores >100). CONCLUSION Increased CAC imparts an increased CHD risk in younger and elderly individuals. CAC is highly predictive of CHD event risk across all age groups, suggesting that once CAC is known chronologic age has less importance. The utility of CAC scoring as a risk-stratification tool extends to both younger and elderly patients.

DIFFERENTIAL IMPACT OF TRADITIONAL RISK FACTORS FOR PREDICTING THE PROBABILITY OF OBSTRUCTIVE CORONARY ARTERY DISEASE IN MEN AND WOMEN WITH CHEST PAIN: RESULTS FROM THE MULTINATIONAL CONFIRM REGISTRY

Whether certain traditional risk factors (RFs) provide greater predictive strength for obstructive coronary artery disease (≥50p diameter stenosis, “OCAD”) in patients with chest pain is unknown. From 8106 consecutive patients (mean age 58 years, 3999 men) without CAD history

DOES NONCALCIFIED PLAQUE IMPROVE THE DIAGNOSTIC AND PROGNOSTIC UTILITY OF CORONARY CT ANGIOGRAPHY? A STUDY OF PROPENSITY-MATCHED INDIVIDUALS WITH SIMILAR CORONARY CALCIUM SCORES FROM THE PROSPECTIVE MULTICENTER INTERNATIONAL CONFIRM REGISTRY

Calcified plaque (CP) on non-contrast coronary calcium scoring (CCS) robustly predicts future major adverse cardiac events (MACE). Noncalcified plaques (NCP) are detectable by contrast-enhanced coronary CT angiography (CCTA), but whether NCP improves diagnostic and prognostic utility beyond CCS