Fluctuating Physical Function and Health: Their Role at the End of Life.

BACKGROUND: Our recent research suggests that a fluctuating trajectory, previously thought to be the experience of those dying with heart failure or chronic lung disease, may not accurately characterize the end of life for these patients. OBJECTIVE: We sought to further examine health and function to investigate whether other measures or a different time frame captures the purported exacerbation/recovery trajectory associated with these diseases. DESIGN: Function and health data were collected prospectively at six-month intervals for 17 years during the Heath, Aging and Body Composition Study. SUBJECTS AND MEASURES: We analyzed self-reported mobility, health status, and health care utilization for 1410 decedents, defining high fluctuations as transitions in two or more adjacent assessment pairs during the last three years of life. RESULTS: Among decedents, only 207 (14.7%) reported two or more changes in mobility during the last three years of life; and 586 (41.6%) reported more than two transitions in self-reported health during the period. This fluctuation was not associated with any clinical condition in the three years before death, but decedents with chronic heart failure or chronic lung disease reported significantly more changes in mobility (odds ratio = 1.15, p = 0.025) for a longer follow-up period. Decedents with heart failure were also more likely to report hospital stays in the last three years of life. CONCLUSIONS: Fluctuations in mobility and self-reported health do not differ by clinical condition in the three years before death, but people dying with chronic heart failure or chronic lung disease are more frequently hospitalized during this period and experience more unstable mobility for a longer period of observation.

Racial Differences in Cause-Specific Mortality Between Community-Dwelling Older Black and White Adults.

OBJECTIVES: To understand which causes of death are higher in black than white community-dwelling older adults and determine whether differences in baseline risk factors explain racial differences in mortality. DESIGN: Longitudinal cohort study (Health, Aging, and Body Composition Study). SETTING: Pittsburgh, Pennsylvania; and Memphis, Tennessee. PARTICIPANTS: Black and white men and women aged 70 to 79 during recruitment (N=3,075; 48% men, 42% black) followed for a median of 13 years. MEASUREMENTS: A committee of physicians adjudicated cause of death, which was categorized as cardiovascular disease (CVD), stroke, cancer, dementia, pulmonary, infection, kidney, or other causes. Using competing risks regression, we examined whether known risk factors at baseline (demographic characteristics, smoking, body mass index, chronic diseases, physical function, cognition) could explain racial differences in cause-specific mortality risk. RESULTS: During follow-up, 1,991 (65%) participants died. Black participants died at higher rates from cancer (hazard ratio (HR)=1.36, 95% confidence interval (CI)=1.14-1.63), kidney disease (HR=2.09, 95% CI=1.16-3.74), stroke (HR=1.31, 95% CI=0.98-1.76); and CVD (HR=1.16, 95% CI=0.98-1.37). Poorer physical and cognitive performance at baseline among black participants explained most of the racial difference in risks of dying from kidney disease, stroke, and CVD but not cancer. When examining types of cancer deaths, black participants died at higher rates from multiple myeloma, pancreatic cancer, and prostate cancer, which baseline risk factors did not explain either. CONCLUSION: Factors contributing to poorer physical and cognitive performance in similarly aged black men and women could be targets to reduce excess mortality from CVD, stroke, and kidney disease. More work is needed to identify factors contributing to cancer mortality disparities.

Effect of Aspirin on All-Cause Mortality in the Healthy Elderly.

BACKGROUND: In the primary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, now published in the Journal, we report that the daily use of aspirin did not provide a benefit with regard to the primary end point of disability-free survival among older adults. A numerically higher rate of the secondary end point of death from any cause was observed with aspirin than with placebo. METHODS: From 2010 through 2014, we enrolled community-dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. Deaths were classified according to the underlying cause by adjudicators who were unaware of trial-group assignments. Hazard ratios were calculated to compare mortality between the aspirin group and the placebo group, and post hoc exploratory analyses of specific causes of death were performed. RESULTS: Of the 19,114 persons who were enrolled, 9525 were assigned to receive aspirin and 9589 to receive placebo. A total of 1052 deaths occurred during a median of 4.7 years of follow-up. The risk of death from any cause was 12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group (hazard ratio, 1.14; 95% confidence interval [CI], 1.01 to 1.29). Cancer was the major contributor to the higher mortality in the aspirin group, accounting for 1.6 excess deaths per 1000 person-years. Cancer-related death occurred in 3.1% of the participants in the aspirin group and in 2.3% of those in the placebo group (hazard ratio, 1.31; 95% CI, 1.10 to 1.56). CONCLUSIONS: Higher all-cause mortality was observed among apparently healthy older adults who received daily aspirin than among those who received placebo and was attributed primarily to cancer-related death. In the context of previous studies, this result was unexpected and should be interpreted with caution. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).

Development of a standardized definition for clinically significant bleeding in the ASPirin in Reducing Events in the Elderly (ASPREE) trial.

BACKGROUND: Bleeding is the major risk of aspirin treatment, especially in the elderly. A consensus definition for clinically significant bleeding (CSB) in aspirin primary prevention trials is lacking in the literature. METHODS: This paper details the development, modification, application, and quality control of a definition for clinically significant bleeding in the ASPirin in Reducing Events in the Elderly (ASPREE) trial, a primary prevention trial of aspirin in 19,114 community-dwelling elderly men and women. In ASPREE a confirmed bleeding event needed to meet criteria both for substantiated bleeding and clinical significance. Substantiated bleeding was defined as: 1) observed bleeding, 2) a reasonable report of symptoms of bleeding, 3) medical, nursing or paramedical report, or 4) imaging evidence. Bleeding was defined as clinically significant if it: 1) required transfusion of red blood cells, 2) required admission to the hospital for >24 h, or prolonged a hospitalization, with bleeding as the principal reason, 3) required surgery to stop the bleeding, or 4) resulted in death. Bleeding sites were subclassified as upper gastrointestinal, lower gastrointestinal, intracranial (hemorrhagic stroke, subarachnoid hemorrhage, subdural hematoma, extradural hematoma, or other), or other sites. Potential events were retrieved from medical records, self-report or notification from treating doctors. Two reviewers adjudicated each event using electronic adjudication software, and discordant cases were reviewed by a third reviewer. Adjudication rules evolved to become more strictly defined as the trial progressed and decision rules were added to assist with frequent scenarios such as post-operative bleeding. CONCLUSIONS: This paper provides a detailed methodologic description of the development of a standardized definition for clinically significant bleeding and provides a benchmark for development of a consensus definition for future aspirin primary prevention trials. TRIAL REGISTRATION: ASPREE is registered on the International Standard Randomized Controlled Trial Number Register (ISRCTN83772183) and on clinicaltrials.gov (NCT01038583).

Trajectories of peripheral interleukin-6, structure of the hippocampus, and cognitive impairment over 14 years in older adults.

We aimed to investigate if trajectory components (baseline level, slope, and variability) of peripheral interleukin-6 (IL-6) over time were related to cognitive impairment and smaller hippocampal volume and if hippocampal volume explained the associations between IL-6 and cognitive impairment. Multivariable regression models were used to test the association between IL-6 trajectory components with change in neuroimaging measures of the hippocampus and with cognitive impairment among 135 older adults (70-79 years at baseline) from the Healthy Brain Project over 14 years. IL-6 variability was positively associated with cognitive impairment (odds ratio [OR] = 5.86, 95% confidence interval [CI]: 1.24, 27.61) and with greater decrease per year of gray matter volume of the hippocampus (ß = -0.008, standard error = 0.004, p = 0.03). After adjustment for hippocampal volume, the OR of cognitive impairment decreased for each unit of IL-6 variability and CIs widened (OR = 4.36, 95% CI: 0.67, 28.29). Neither baseline levels nor slopes of IL-6 were related to cognitive impairment or hippocampal volume. We believe this has potential clinical and public health implications by suggesting adults with stable levels of peripheral IL-6 may be better targets for intervention studies for slowing or preventing cognitive decline.

Infection hospitalization increases risk of dementia in the elderly.

OBJECTIVES: Severe infections, often requiring ICU admission, have been associated with persistent cognitive dysfunction. Less severe infections are more common and whether they are associated with an increased risk of dementia is unclear. We determined the association of pneumonia hospitalization with risk of dementia in well-functioning older adults. DESIGN: Secondary analysis of a randomized multicenter trial to determine the effect of Gingko biloba on incident dementia. SETTING: Five academic medical centers in the United States. SUBJECTS: Healthy community volunteers (n = 3,069) with a median follow-up of 6.1 years. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: We identified pneumonia hospitalizations using International Classification of Diseases, 9th Edition-Coding Manual codes and validated them in a subset. Less than 3% of pneumonia cases necessitated ICU admission, mechanical ventilation, or vasopressor support. Dementia was adjudicated based on neuropsychological evaluation, neurological examination, and MRI. Two hundred twenty-one participants (7.2%) incurred at least one hospitalization with pneumonia (mean time to pneumonia = 3.5 yr). Of these, dementia was developed in 38 (17%) after pneumonia, with half of these cases occurring 2 years after the pneumonia hospitalization. Hospitalization with pneumonia was associated with increased risk of time to dementia diagnosis (unadjusted hazard ratio = 2.3; CI, 1.6-3.2; p < 0.0001). The association remained significant when adjusted for age, sex, race, study site, education, and baseline mini-mental status examination (hazard ratio = 1.9; CI, 1.4-2.8; p < 0.0001). Results were unchanged when additionally adjusted for smoking, hypertension, diabetes, heart disease, and preinfection functional status. Results were similar using propensity analysis where participants with pneumonia were matched to those without pneumonia based on age, probability of developing pneumonia, and similar trajectories of cognitive and physical function prior to pneumonia (adjusted prevalence rates, 91.7 vs 65 cases per 1,000 person-years; adjusted prevalence rate ratio = 1.6; CI, 1.06-2.7; p = 0.03). Sensitivity analyses showed that the higher risk also occurred among those hospitalized with other infections. CONCLUSION: Hospitalization with pneumonia is associated with increased risk of dementia.

NK-like T cells and plasma cytokines, but not anti-viral serology, define immune fingerprints of resilience and mild disability in exceptional aging.

Exceptional aging has been defined as maintenance of physical and cognitive function beyond the median lifespan despite a history of diseases and/or concurrent subclinical conditions. Since immunity is vital to individual fitness, we examined immunologic fingerprint(s) of highly functional elders. Therefore, survivors of the Cardiovascular Health Study in Pittsburgh, Pennsylvania, USA were recruited (n = 140; mean age = 86 years) and underwent performance testing. Blood samples were collected and examined blindly for humoral factors and T cell phenotypes. Based on results of physical and cognitive performance testing, elders were classified as "impaired" or "unimpaired", accuracy of group assignment was verified by discriminant function analysis. The two groups showed distinct immune profiles as determined by factor analysis. The dominant immune signature of impaired elders consisted of interferon (IFN)-γ, interleukin (IL)-6, tumor necrosis factor-α, and T cells expressing inhibitory natural killer-related receptors (NKR) CD158a, CD158e, and NKG2A. In contrast, the dominant signature of unimpaired elders consisted of IL-5, IL-12p70, and IL-13 with co-expression of IFN-γ, IL-4, and IL-17, and T cells expressing stimulatory NKRs CD56, CD16, and NKG2D. In logistic regression models, unimpaired phenotype was predicted independently by IL-5 and by CD4(+)CD28(null)CD56(+)CD57(+) T cells. All elders had high antibody titers to common viruses including cytomegalovirus. In cellular bioassays, T cell receptor (TCR)-independent ligation of either CD56 or NKG2D elicited activation of T cells. Collectively, these data demonstrate the importance of immunological parameters in distinguishing between health phenotypes of older adults. NKR(+) T cells and cytokine upregulation indicate a unique physiologic environment in old age. Correlation of particular NKR(+) T cell subsets and IL-5 with unimpaired performance, and NKR-driven TCR-independent activation of T cells suggest novel immunopathway(s) that could be exploited to improve immunity in old age.

Longitudinal changes in adiponectin and inflammatory markers and relation to survival in the oldest old: the Cardiovascular Health Study All Stars study.

BACKGROUND: Adiponectin has anti-inflammatory properties, and its production is suppressed by inflammatory factors. Although elevated levels of adiponectin and inflammatory markers each predict mortality in older adults, the implications of their interdependent actions have not been examined. METHODS: We investigated the joint associations of levels and interval changes in adiponectin, C-reactive protein (CRP), and interleukin 6 (IL-6) with risk of death in 840 older adults participating in a population-based study. Adiponectin, CRP, and IL-6 were measured in samples collected 8.9 (8.2-9.8) years apart, and all-cause mortality was subsequently ascertained (n = 176). RESULTS: Interval changes and end levels of adiponectin, CRP, and IL-6 showed mostly positive, independent associations with mortality, without evidence of multiplicative interaction. Joint models, however, showed an U-shaped relationship between end level of adiponectin and outcome (hazard ratio [HR] [95% CI] = 0.72 [0.52-0.99] per standard deviation [SD] for levels <20.0 mg/L; HR = 1.91 [1.61-3.44] per SD for levels ≥20.0 mg/L). Participants with the greatest longitudinal increases (upper quartile) in both adiponectin and inflammatory markers had a higher risk of death (HR = 2.85 [1.78-4.58]) than those with large increases in adiponectin alone (HR = 1.87 [1.20-2.92]) (p = .043), but not inflammatory markers alone (HR = 2.48 [1.67-3.67]) (p = .55), as compared with smaller changes for both. CONCLUSION: Higher levels or interval change in adiponectin and inflammatory markers predict increased mortality in older persons independent of each other, although for adiponectin, the association appears inverse below 20 mg/L. These findings suggest that inflammatory and noninflammatory mechanisms governing aging-related decline operate in parallel and provide a potential explanation for paradoxical adiponectin-outcome associations reported previously.

Patterns and predictors of recovery from exhaustion in older adults: the cardiovascular health study.

OBJECTIVES: To estimate the likelihood of, and factors associated with, recovery from exhaustion in older adults. DESIGN: Secondary analysis of a cohort study. SETTING: Six annual examinations in four U.S. communities. PARTICIPANTS: Four thousand five hundred eighty-four men and women aged 69 and older. MEASUREMENTS: Exhaustion was considered present when a participant responded "a moderate amount" or "most of the time" to either of two questions: "How often have you had a hard time getting going?" and "How often does everything seem an effort?" RESULTS: Of the 964 participants who originally reported exhaustion, 634 (65.8%) were exhaustion free at least once during follow-up. When data from all time points were considered, 48% of those who reported exhaustion were exhaustion free the following year. After adjustment for age, sex, race, education, and marital status, 1-year recovery was less likely in individuals with worse self-rated health and in those who were taking six or more medications or were obese, depressed, or had musculoskeletal pain or history of stroke. In proportional hazards models, the following risk factors were associated with more persistent exhaustion over 5 years: poor self-rated health, six or more medications, obesity, and depression. Recovery was not less likely in participants with a history of cancer or heart disease. CONCLUSION: Exhaustion is common in old age but is dynamic, even in those with a history of cancer and congestive heart failure. Recovery is especially likely in seniors who have a positive perception of their overall health, take few medications, and are not obese or depressed. These findings support the notion that resiliency is associated with physical and psychological well-being.

Does Ginkgo biloba reduce the risk of cardiovascular events?

BACKGROUND: Cardiovascular disease (CVD) was a preplanned secondary outcome of the Ginkgo Evaluation of Memory Study. The trial previously reported that Ginkgo biloba had no effect on the primary outcome, incident dementia. METHODS AND RESULTS: The double-blind trial randomly assigned 3069 participants over 75 years of age to 120 mg of G biloba EGb 761 twice daily or placebo. Mean follow-up was 6.1 years. The identification and classification of CVD was based on methods used in the Cardiovascular Health Study. Differences in time to event between G biloba and placebo were evaluated using Cox proportional hazards regression adjusted for age and sex. There were 355 deaths in the study, 87 due to coronary heart disease with no differences between G biloba and placebo. There were no differences in incident myocardial infarction (n=164), angina pectoris (n=207), or stroke (151) between G biloba and placebo. There were 24 hemorrhagic strokes, 16 on G biloba and 8 on placebo (not significant). There were only 35 peripheral vascular disease events, 12 (0.8%) on G biloba and 23 (1.5%) on placebo (P=0.04, exact test). Most of the peripheral vascular disease cases had either vascular surgery or amputation. CONCLUSIONS: There was no evidence that G biloba reduced total or CVD mortality or CVD events. There were more peripheral vascular disease events in the placebo arm. G biloba cannot be recommended for preventing CVD. Further clinical trials of peripheral vascular disease outcomes might be indicated. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00010803.

Agreement between nosologist and cardiovascular health study review of deaths: implications of coding differences.

OBJECTIVES: To compare nosologist coding of underlying cause of death according to the death certificate with adjudicated cause of death for subjects aged 65 and older in the Cardiovascular Health Study (CHS). DESIGN: Observational. SETTING: Four communities: Forsyth County, North Carolina (Wake Forest University); Sacramento County, California (University of California at Davis); Washington County, Maryland (Johns Hopkins University); and Pittsburgh, Pennsylvania (University of Pittsburgh). PARTICIPANTS: Men and women aged 65 and older participating in CHS, a longitudinal study of coronary heart disease and stroke, who died through June 2004. MEASUREMENTS: The CHS centrally adjudicated underlying cause of death for 3,194 fatal events from June 1989 to June 2004 using medical records, death certificates, proxy interviews, and autopsies, and results were compared with underlying cause of death assigned by a trained nosologist based on death certificate only. RESULTS: Comparison of 3,194 CHS versus nosologist underlying cause of death revealed moderate agreement except for cancer (kappa=0.91, 95% confidence interval (CI)=0.89-0.93). kappas varied according to category (coronary heart disease, kappa=0.61, 95% CI=0.58-0.64; stroke, kappa=0.59, 95% CI=0.54-0.64; chronic obstructive pulmonary disease, kappa=0.58, 95% CI=0.51-0.65; dementia, kappa=0.40, 95% CI=0.34-0.45; and pneumonia, kappa=0.35, 95% CI=0.29-0.42). Differences between CHS and nosologist coding of dementia were found especially in older ages in the sex and race categories. CHS attributed 340 (10.6%) deaths due to dementia, whereas nosologist coding attributed only 113 (3.5%) to dementia as the underlying cause. CONCLUSION: Studies that use only death certificates to determine cause of death may result in misclassification and potential bias. Changing trends in cause-specific mortality in older individuals may be a function of classification process rather than incidence and case fatality.

Death rates and causes of death after bariatric surgery for Pennsylvania residents, 1995 to 2004.

BACKGROUND: Bariatric surgery has emerged as the most effective treatment for class III obesity (body mass index, >or=40). The number of operations continues to increase. We measured case fatality and death rates by time since operation, sex, age, specific causes of death, and mortality rates. DESIGN AND SETTING: Data on all bariatric operations performed on Pennsylvania residents between January 1, 1995, and December 31, 2004, were obtained from the Pennsylvania Health Care Cost and Containment Council. Matching mortality data were obtained from the Division of Vital Records, Pennsylvania State Department of Health. OUTCOME MEASURES: Age- and sex-specific death rates after bariatric surgery. RESULTS: There were 440 deaths after 16 683 operations (2.6%). Age-specific death rates were much higher in men than in women and increased with age. Age- and sex-specific death rates after bariatric surgery were substantially higher than comparable rates for the age- and sex-matched Pennsylvania population. The 1-year case fatality rate was approximately 1% and nearly 6% at 5 years. Less than 1% of deaths occurred within the first 30 days. Fatality increased substantially with age (especially among those > 65 years), with little evidence of change over time. Coronary heart disease was the leading cause of death overall, being cited as the cause of death in 76 patients (19.2%). Therapeutic complications accounted for 38 of 150 natural deaths within the first 30 days, including pulmonary embolism in 31 (20.7%), coronary heart disease in 26 (17.3%), and sepsis in 17 (11.3%). CONCLUSIONS: There was a substantial excess of deaths owing to suicide and coronary heart disease. Careful monitoring of bariatric surgical procedures and more intense follow-up could likely reduce the long-term case fatality rate in this patient population.