Wildon R. Farwell

Adverse events associated with testosterone administration.

BACKGROUND Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied. METHODS Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group. RESULTS A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load. CONCLUSIONS In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy. (ClinicalTrials.gov number, NCT00240981.)

Prevalence and Characteristics of Tinnitus among US Adults

BACKGROUND Tinnitus is common; however, few risk factors for tinnitus are known. METHODS We examined cross-sectional relations between several potential risk factors and self-reported tinnitus in 14,178 participants in the 1999-2004 National Health and Nutrition Examination Surveys, a nationally representative database. We calculated the prevalence of any and frequent (at least daily) tinnitus in the overall US population and among subgroups. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) after adjusting for multiple potential confounders. RESULTS Approximately 50 million US adults reported having any tinnitus, and 16 million US adults reported having frequent tinnitus in the past year. The prevalence of frequent tinnitus increased with increasing age, peaking at 14.3% between 60 and 69 years of age. Non-Hispanic whites had higher odds of frequent tinnitus compared with other racial/ethnic groups. Hypertension and former smoking were associated with an increase in odds of frequent tinnitus. Loud leisure-time, firearm, and occupational noise exposure also were associated with increased odds of frequent tinnitus. Among participants who had an audiogram, frequent tinnitus was associated with low-mid frequency (OR 2.37; 95% CI, 1.76-3.21) and high frequency (OR 3.00; 95% CI, 1.78-5.04) hearing impairment. Among participants who were tested for mental health conditions, frequent tinnitus was associated with generalized anxiety disorder (OR 6.07; 95% CI, 2.33-15.78) but not major depressive disorder (OR 1.58; 95% CI, 0.54-4.62). CONCLUSIONS The prevalence of frequent tinnitus is highest among older adults, non-Hispanic whites, former smokers, and adults with hypertension, hearing impairment, loud noise exposure, or generalized anxiety disorder. Prospective studies of risk factors for tinnitus are needed.

The Association Between Statins and Cancer Incidence in a Veterans Population

BACKGROUND Meta-analyses of trials of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors or statins for cardiovascular disease prevention have failed to show any statistically significant benefit of statins for cancer prevention. However, these trials included relatively young participants, who develop few cancers, and their follow-up periods may have been too short to detect an association between statin use and cancer incidence. We investigated this association in a population of veterans. METHODS We identified patients using antihypertensive medications but no cholesterol-lowering medications (n = 25,594) and patients using statins (n = 37,248) who were enrolled in the Veterans Affairs New England Healthcare System between January 1, 1997, and December 31, 2005. Age- and multivariable-adjusted Cox proportional hazards models were used to calculate the hazard ratio (HR) and its 95% confidence interval (CI) for cancer incidence, excluding nonmelanoma skin cancer, among patients taking statins compared with patients taking antihypertensive medications and among patients grouped by statin dose (as equivalent simvastatin dose). All statistical tests were two-sided. RESULTS The absolute incidence of total cancers was 9.4% among statin users and 13.2% among nonusers (difference = 3.8%, 95% CI = 3.3% to 4.3%, P(difference) < .001). Statin users had a statistically significant lower risk for total cancer than nonusers after adjustment for age (HR = 0.76, 95% CI = 0.73 to 0.80) and multiple potential confounders (HR = 0.74, 95% CI = 0.70 to 0.78). After multivariable adjustment, a statistically significantly decreased risk of all cancers was also associated with increasing statin use (P(trend) < .001). CONCLUSIONS Patients using statins may be at lower risk for developing cancer. Additional observational studies and randomized trials of statins for cancer prevention are warranted.

Clinical Meaningfulness of the Changes in Muscle Performance and Physical Function Associated With Testosterone Administration in Older Men With Mobility Limitation

CONTEXT Testosterone in Older Men with Mobility Limitations Trial determined the effects of testosterone on muscle performance and physical function in older men with mobility limitation. Trials Data and Safety Monitoring Board recommended enrollment cessation due to increased frequency of adverse events in testosterone arm. The changes in muscle performance and physical function were evaluated in relation to participants perception of change. METHODS Men aged 65 years and older, with mobility limitation, total testosterone 100-350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Primary outcome was leg-press strength. Secondary outcomes included chest-press strength, stair-climb, 40-m walk, muscle mass, physical activity, self-reported function, and fatigue. Proportions of participants exceeding minimally important difference in study arms were compared. RESULTS Of 209 randomized participants, 165 had follow-up efficacy measures. Mean (SD) age was 74 (5.4) years and short physical performance battery score 7.7 (1.4). Testosterone arm exhibited greater improvements in leg-press strength, chest-press strength and power, and loaded stair-climb than placebo. Compared with placebo, significantly greater proportion of men receiving testosterone improved their leg-press and chest-press strengths (43% vs 18%, p = .01) and stair-climbing power (28% vs 10%, p = .03) more than minimally important difference. Increases in leg-press strength and stair-climbing power were associated with changes in testosterone levels and muscle mass. Physical activity, walking speed, self-reported function, and fatigue did not change. CONCLUSIONS Testosterone administration in older men with mobility limitation was associated with patient-important improvements in muscle strength and stair-climbing power. Improvements in muscle strength and only some physical function measures should be weighed against the risk of adverse events in this population.

Primary Care Visit Duration and Quality: Does Good Care Take Longer?

BACKGROUND It is unclear if increasing pressure on primary care physicians to be more efficient has affected visit duration or quality of care. We sought to describe changes in the duration of adult primary care visits and in the quality of care provided during these visits and to determine whether quality of care is associated with visit duration. METHODS We conducted a retrospective analysis of visits by adults 18 years or older to a nationally representative sample of office-based primary care physicians in the United States. RESULTS Between 1997 and 2005, US adult primary care visits to physicians increased from 273 million to 338 million annually, or 10% on a per capita basis. The mean visit duration increased from 18.0 to 20.8 minutes (P < .001 for trend). Visit duration increased by 3.4 minutes for general medical examinations and for the 3 most common primary diagnoses of diabetes mellitus (4.2 minutes, P = .002 for trend), essential hypertension (3.7 minutes, P < .001 for trend), and arthropathies (5.9 minutes, P < .001 for trend). Comparing the early period (1997-2001) with the late period (2002-2005), quality of care improved for 1 of 3 counseling or screening indicators and for 4 of 6 medication indicators. Providing appropriate counseling or screening generally took 2.6 to 4.2 minutes. Providing appropriate medication therapy was not associated with longer visit duration. CONCLUSIONS Adult primary care visit frequency, quality, and duration increased between 1997 and 2005. Modest relationships were noted between visit duration and quality of care. Providing counseling or screening required additional physician time, but ensuring that patients were taking appropriate medications seemed to be independent of visit duration.

Cholinesterase inhibitors and incidence of bradycardia in patients with dementia in the veterans affairs new England healthcare system.

OBJECTIVES: To quantify the association between cholinesterase inhibitors (ChE‐Is) and a new diagnosis of bradycardia and to evaluate the clinical significance of bradycardia.

Statins and Prostate Cancer Diagnosis and Grade in a Veterans Population

BACKGROUND Although prostate cancer is commonly diagnosed, few risk factors for high-grade prostate cancer are known and few prevention strategies exist. Statins have been proposed as a possible treatment to prevent prostate cancer. METHODS Using electronic and administrative files from the Veterans Affairs New England Healthcare System, we identified 55,875 men taking either a statin or antihypertensive medication. We used age- and multivariable-adjusted Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer incidence among patients taking statins (n = 41,078) compared with patients taking antihypertensive medications (n = 14,797). We performed similar analyses for all lipid parameters including total cholesterol examining each lipid parameter as a continuous variable and by quartiles. All statistical tests were two-sided. RESULTS Compared with men taking an antihypertensive medication, statin users were 31% less likely (HR = 0.69, 95% CI = 0.52 to 0.90) to be diagnosed with prostate cancer. Furthermore, statin users were 14% less likely (HR = 0.86, 95% CI = 0.62 to 1.20) to be diagnosed with low-grade prostate cancer and 60% less likely (HR = 0.40, 95% CI = 0.24 to 0.65) to be diagnosed with high-grade prostate cancer compared with antihypertensive medication users. Increased levels of total cholesterol were also associated with both total (HR = 1.02, 95% CI = 1.00 to 1.05) and high-grade (HR = 1.06, 95% CI = 1.02 to 1.10) prostate cancer incidence but not with low-grade prostate cancer incidence (HR = 1.01, 95% CI = 0.98 to 1.04). CONCLUSIONS Statin use is associated with statistically significantly reduced risk for total and high-grade prostate cancer, and increased levels of serum cholesterol are associated with higher risk for total and high-grade prostate cancer. These findings indicate that clinical trials of statins for prostate cancer prevention are warranted.

Comparative Effectiveness Research and Medical Informatics

As is the case for environmental, ecological, astronomical, and other sciences, medical practice and research finds itself in a tsunami of data. This data deluge, due primarily to the introduction of digitalization in routine medical care and medical research, affords the opportunity for improved patient care and scientific discovery. Medical informatics is the subdiscipline of medicine created to make greater use of information in order to improve healthcare. The 4 areas of medical informatics research (information access, structure, analysis, and interaction) are used as a framework to discuss the overlap in information needs of comparative effectiveness research and potential contributions of medical informatics. Examples of progress from the medical informatics literature and the Veterans Affairs Healthcare System are provided.

Randomized Clinical Trial Assessing the Efficacy and Safety of Bromocriptine-QR when Added to Ongoing Thiazolidinedione Therapy in Patients with Type 2 Diabetes Mellitus

Aims: To evaluate the glycemic control efficacy and cardio-metabolic safety of bromocriptine- quick release (Bromocriptine-QR) among subjects with type 2 diabetes who were taking a thiazolidinedione (TZD) at baseline. Methods: A subgroup from the Cycloset Safety trial who were taking a TZD at baseline with or without another oral anti-diabetes medication were randomized to receive additional once daily (morning) bromocriptine-QR (1.6 - 4.8 mg/day) or placebo for up to 52 weeks. Glycemic efficacy analyses were based on intent to treat modified (ITTm) and evaluable per protocol (EPP) population using general linear model after adjusting for baseline covariates and stratified by A1C level of <7.5 of ≥7.5. The odds ratio of participants achieving A1C ≤7% were calculated. Similar analyses for safety were performed on weight and hypoglycemia. Results: In this trial 495 subjects were taking a TZD at baseline and 122 also had a baseline A1C of ≥7.5. For subjects with an A1C of ≥7.5, bromocriptine-QR treatment led to significant reduction in A1C (ITTm -0.81%, p=0.001and EPP -0.91%, p=0.002), fasting plasma glucose (ITTm -21.5 mg/dl, p=0.03 and EPP -20.5 mg/dl, p=0.05), and higher frequency achieving an A1C≤7% (32.1% vs. 15.9%, p=0.05) when compared with placebo. For subjects with a baseline A1C of <7.5, subjects randomized to bromocriptine-QR had a greater odds of having an A1C level of ≤7.0 (OR 2.74, 95% CI 1.45, 5.15; p =0.002). Treatment with bromocriptine-QR had no adverse impact on weight or risk of hypoglycemia. Conclusion: Daily morning bromocriptine-QR added to ongoing TZD treatment for uncontrolled type 2 diabetes improved glycemic control and was well tolerated.

Lack of Cholesterol Awareness among Physicians Who Smoke

Cigarette use is a known risk factor for the development of coronary artery disease (CAD) as it adversely affects HDL cholesterol levels and promotes thrombogenesis. Smoking may also be associated with behavioral characteristics that potentiate the risk of CAD. A lack of cholesterol knowledge would indicate an aversion to a prevention-oriented lifestyle. Thus, our goal was to determine the association between tobacco use and knowledge of self-reported cholesterol among male physicians. Using the 1982 and follow-up questionnaires from the physician health study, we report the changes in the frequencies of awareness of self-reported total cholesterol and cardiovascular risk factors among the 22,067 participants. We classified physicians as being aware of their cholesterol if they reported a cholesterol level and unaware if the question was left unanswered. In 1997, 207 physicians were excluded, as the recorded cholesterol was not interpretable, leaving 21,860 for our follow up analyses. Using unadjusted logistic models, we determined the odds ratios (OR) and 95% confidence intervals (CI) of not reporting a cholesterol level in either 1982 or 1997 for each specified risk factor. We then evaluated whether the lack of cholesterol awareness at both time points was associated with the use of tobacco throughout the study. After 14-years of follow up, cholesterol awareness increased from 35.9 to 58.6 percent. During this period, the frequency of hypertension and hyperlipidemia treatment increased (13.5 to 40.5% and 0.57% to 19.6% respectively), as did the diagnosis of diabetes (2.40 to 7.79%). Behavioral characteristics such as a sedentary lifestyle and obesity also increased (27.8 to 42% and 43.5 to 53.5%, respectively), however the proportion of current smokers deceased from 11.1 to 4.05%. The percentages of individuals being unaware of their cholesterol decreased in all risk factor groups. However, individuals were likely to be unaware of their cholesterol at both time points if they were current smokers (1982 OR 1.44, CI 1.4–1.7; 1997 OR 1.71, CI 1.48–1.97), past smokers (1982 OR 1.12, CI 1.05–1.18; 1997 OR 1.13, CI 1.06–1.20), overweight (BMI 25 kg/m2) or sedentary. In addition, physicians who never quit smoking were likely to be unaware of their cholesterol throughout the study (OR 1.42, CI 1.21–1.67). Cholesterol awareness in general and among those with CAD risk factors improved after 14-years of follow-up. However, the likelihood of being unaware was greater among smokers at both time points. Therefore, smokers do not appear to take advantage of other preventive strategies that would minimize their risk of developing CAD.