Prognosis of older adults with chronic lymphocytic leukemia: A Surveillance, Epidemiology, and End Results-Medicare cohort study.

INTRODUCTION: While prognosis for patients with chronic lymphocytic leukemia (CLL) has improved over time in younger adults, only modest improvements have occurred in older adults. We conducted a descriptive study of prognosis in older adults with CLL. MATERIALS AND METHODS: We used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database from 2003 to 2016. We identified older adults (≥66 years) diagnosed with primary CLL between 2004 and 2015 (Overall Cohort). A subset who initiated CLL-directed therapy during the year following diagnosis was also identified (Treated Cohort). Both cohorts were matched to Medicare beneficiaries without cancer based on age, sex, and region. For each year from 2004 to 2013, three-year survival for patients with CLL and non-cancer comparators was described using Kaplan-Meier analysis. Inverse probability weighted Cox regression models were used to compare survival in the CLL and non-cancer comparator cohorts, accounting for demographic information and comorbidity and frailty indices. Among older adults with CLL, ten-year cause-specific cumulative mortality was estimated using Aalen-Johansen estimators that accounted for competing risks. Predictors of cause-specific mortality, including comorbidity and frailty burden, were assessed using sub-distribution hazards models. RESULTS: In the Overall Cohort, three-year survival increased non-monotonically from 71.4% in 2004 to 73.4% in 2013, with a peak of 74.4% in 2011, and was lower than survival in non-cancer comparators (78.3% in 2004 to 83.2% in 2013). In the Treated Cohort, three-year survival was 56.3% in 2004 and 56.5% in 2013, with a peak of 64.2% in 2011. Cox models suggested that survival in the Treated Cohort was approaching survival in non-cancer comparators after 2011 (hazard ratio = 1.04, 95% confidence interval, 0.93-1.17). Ten-year cumulative mortality was 68.6% in the Overall Cohort and 81.7% in the Treated Cohort, with most deaths attributed to non-CLL causes. In the sub-distribution hazards models, age, year of diagnosis, frailty, and comorbidities were all associated with prognosis. DISCUSSION: Prognosis in older adults has been stable over time and most patients with CLL die from non-CLL causes. CLL-directed treatment decision-making in older adults should consider age-related factors, such as comorbidity and frailty.

Demonstrating that Real World Evidence Is Fit-For-Purpose to Support Labeling: Parallels to Patient Reported Outcomes in the Pursuit of Labeling Claims.

INTRODUCTION: In December 2021, U.S. Food & Drug Administration (FDA) will issue guidance on the use of real-world evidence (RWE) to support new indications or expanded product labeling. While difficult to foresee what FDA will require, learnings can be gleaned from previous paradigm shifts at FDA, such as for patient reported outcomes (PROs) in 2006-2009. METHODS: We contrast published requirements for justifying PROs as fit-for-purpose for a specific labeling claim with a potential approach to justify RWE as fit-for-purpose to support expanded labeling or a new indication. RESULTS: PRO labeling claims require a PRO Evidence Dossier that includes: specific wording of claim, clinical trial hypothesis structure and endpoint model, and justification that the PRO is relevant and meaningful to patients in the target population (content validity) with adequate psychometric properties. FDA's 2018 RWE Framework outlined critical considerations for using RWE to support regulatory decisions, including data quality, relevancy, provenance, and transparency. Strong parallels exist between the evidence required to justify that PROs are fit-for-purpose to support specific labeling claims and evidence to justify RWE as fit-for-purpose for specific research questions and labeling. Early discussion with FDA is encouraged. CONCLUSION: Drawing on parallels with use of PROs in labeling, RWE for regulatory purposes should be evaluated within the context of specific labeling or indication, specific study design and analysis plans, and the data attributes of data source. Sponsors seeking a new indication or labeling expansion based on RWE should justify that a specific data source and specific study design are fit-for-purpose.

Characteristics of Elderly Patients Initiating Sitagliptin or Non-DPP-4-Inhibitor Oral Antihyperglycemic Agents: Analysis of a Cross-Sectional US Claims Database.

INTRODUCTION: Previous analyses concluded that patients initiating treatment with sitagliptin are older and have more comorbidities than patients initiating treatment with other oral antihyperglycemic agents (OAHAs). However, these studies focused on the general population or subjects ≤ 65 years of age. We sought to compare differences in baseline characteristics of elderly patients (≥ 65 years of age) with T2DM initiating sitagliptin vs. non-DPP-4 inhibitor (non-DPP-4i) OAHA in the MarketScan® Medicare Supplemental Database. METHODS: Relevant patients were identified in the MarketScan® Medicare Supplemental Database and categorized according to the complexity of their antihyperglycemic treatment: initiating monotherapy, escalating to dual combination therapy, or escalating to triple combination therapy. Within each category, the comparison between patients initiating use of sitagliptin or non-DPP-4i OAHA was made within three age groups: 65-74, 75-84, and ≥ 85 years. Gender and comorbidity recorded within the 12 months prior to the index date (date of initiation/escalation of treatment) were assessed as baseline characteristics in each group. Between-treatment group differences in each covariate were compared using standardized differences. RESULTS: Patients with T2DM who initiated treatment with sitagliptin tended to be older and were more likely to have a pre-treatment history of arrhythmia, congestive heart failure, peripheral vascular disease, renal failure, and stroke than those initiating non-DPP-4i OAHAs, with the most pronounced differences observed between patients initiating monotherapy in all three age groups. As treatment complexity advanced to dual combination therapy, the differences were attenuated and mostly observed in the 75-84 and ≥ 85 age groups. In patients aged 65-74 years initiating triple therapy, no differences were observed between groups. CONCLUSION: Patients ≥ 65 years with T2DM initiating sitagliptin tend to be older and have more comorbidities than those prescribed other classes of OAHA. Appropriate adjustment is required to minimize the impact of potential confounding and channeling bias in any comparative analyses including users of sitagliptin. FUNDING: Merck & Co., Inc., Kenilworth, NJ, USA.

Identification of impaired fasting glucose, healthcare utilization and progression to diabetes in the UK using the Clinical Practice Research Datalink (CPRD).

PURPOSE: Few studies have examined patients with prediabetes in usual, "real-world" clinical practice settings. Among patients with impaired fasting glucose (IFG), we aimed to describe the rates of progression to diabetes and to examine the long-term reduction in diabetes risk associated with regression to normoglycemia at 1 year. METHODS: The UK-based study included 120 055 non-diabetic patients in Clinical Practice Research Datalink from 2001 to 2012 aged 25+ years and with ≥1 fasting plasma glucose (FPG) test between ≥6.1 and <7.0 mmol/l indicating IFG who were followed for progression to diabetes. In a subgroup of 45 167 patients with IFG with subsequent FPG results 1 year later, we assessed the 1-year glycemic status change and estimated the relative hazard of diabetes comparing patients with regression to normoglycemia (IFG-normoglycemia) to those who remained in IFG (IFG-IFG) using a multivariable Cox model. RESULTS: Among patients with IFG with over 414 649 person-years of follow-up, 52% received a subsequent FPG test, and 10% developed diabetes within 1 year after recognition of IFG. The incidence rate of diabetes was 5.86 (95% CI: 5.78 to 5.93) per 100 person-years. In the subgroup analysis, 31% of these patients remained in IFG, while 53% and 16% converted to normoglycemia or diabetes, respectively. The adjusted hazard ratio of developing diabetes was 0.33 (95% CI: 0.31 to 0.35) comparing IFG-normoglycemia to IFG-IFG. CONCLUSIONS: IFG is a high-risk state for diabetes. Regression to normoglycemia from IFG strongly reduces the long-term risk of developing diabetes. Our study also shows the feasibility of identifying patients with IFG in the Clinical Practice Research Datalink. Copyright © 2016 John Wiley & Sons, Ltd.

Airflow obstruction, lung function, and incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Reduced low forced expiratory volume in 1 second (FEV1) is reportedly associated with an increased risk of atrial fibrillation (AF). Extant reports do not provide separate estimates for never smokers or for blacks, who incongruously have lower AF incidence than whites. METHODS AND RESULTS: We examined 15 004 middle-aged blacks and whites enrolled in the Atherosclerosis Risk in Communities (ARIC) cohort study. Standardized spirometry data were collected at the baseline examination. Incident AF was identified from the first among the following: International Classification of Diseases codes for AF on hospital discharge records or death certificates or 12-lead ECGs performed during 3 triennial follow-up visits. Over an average follow-up of 17.5 years, a total of 1691 participants (11%) developed new-onset AF. The rate of incident AF was inversely associated with FEV1 in each of the 4 race and sex groups. After multivariable adjustment for traditional cardiovascular disease risk factors and height, hazard ratios of AF comparing the lowest with the highest quartile of FEV1 were 1.37 (95% confidence interval, 1.02-1.83) for white women, 1.49 (95% confidence interval, 1.16-1.91) for white men, 1.63 (95% confidence interval, 1.00-2.66) for black women, and 2.36 (95% confidence interval, 1.30-4.29) for black men. The above associations were observed across all smoking status categories. Moderate/severe airflow obstruction (FEV1/forced vital capacity <0.70 and FEV1 < 80% of predicted value) was also associated with higher AF incidence. CONCLUSIONS: In this large population-based study with a long-term follow-up, reduced FEV1 and obstructive respiratory disease were associated with a higher AF incidence after adjustment for measured confounders.

The potentially modifiable burden of incident heart failure due to obesity: the atherosclerosis risk in communities study.

The authors estimated the generalized impact fraction (GIF) for heart failure (HF) related to obesity, representing the proportion of incident HF events that could be prevented from reductions in obesity and/or overweight. The Atherosclerosis Risk in Communities Study is a biracial population-based cohort study of persons aged 45-64 years from 4 US communities with a median 14 years of follow-up (1987-2003) for incident, hospitalized, or fatal HF. Body mass index (BMI; weight (kg)/height (m)(2)) was measured at baseline (1987-1989) and categorized as normal weight (BMI <25), overweight (BMI 25-29.9), or obese (BMI ≥30). After exclusion of prevalent HF, missing BMI, and poorly represented racial groups, the sample size was 14,642. The GIF and attributable fraction were calculated using a case-load weighted-sum method. A 95% distribution of the GIF was estimated from bootstrapped data sets. A 30% hypothetical reduction in obesity/overweight would potentially prevent 8.5% (95% simulation interval: 6.1, 10.7) of incident HF events. The attributable fraction, which assumes complete elimination of obesity/overweight, was 28% (95% simulation interval: 20, 36)-approximately 3 times larger than the most optimistic GIF calculated here. Investigators studying exposures that are unlikely to be eradicated given current prevention efforts, such as obesity, should consider estimating the GIF to avoid overestimates of population impact.

Association of multiple anthropometrics of overweight and obesity with incident heart failure: the Atherosclerosis Risk in Communities study.

BACKGROUND: The association of central adiposity with incident heart failure (HF) has yet to be studied in a large population-based study. METHODS AND RESULTS: The Atherosclerosis Risk in Communities study is an ongoing biracial population-based cohort of those aged 45 to 64 years from 4 US communities with 16 years' median follow-up for incident, hospitalized, or fatal HF. Waist-hip ratio, waist circumference, and body mass index (BMI) were measured at baseline (1987-1989). After exclusions, the sample size was 14 641. BMI was categorized as <25, 25 to 29.9, and >or=30 kg/m(2). Waist circumference and waist-hip ratio were divided into gender-specific tertiles. A first occurrence of International Classification of Diseases, 9th Revision, Clinical Modification, codes of HF, either hospital discharge (428.0 to 428.9; n=1451) or on a death certificate (428.0 to 428.9 or I50.0 to I50.9; n=77) was considered an HF event. Cox models were adjusted for alcohol use, smoking, age, center, and educational level. The adjusted hazard ratios for the highest category (obese) compared with the lowest were well above 1.0 for all 3 anthropometric measures (hazard ratio for 3rd versus 1st tertile of waist-hip ratio: 2.27 [1.71, 3.02] for white women; 3.24 [2.25, 4.65] for black women; 2.46 [1.95, 3.09] for white men; and 2.63 [1.90, 3.65] for black men). Hazard ratios for overweight were lower in magnitude, suggesting a graded response between body size and HF. CONCLUSIONS: Obesity and overweight, as measured by 3 different anthropometrics, were associated with incident HF in the Atherosclerosis Risk in Communities cohort. The current study does not support the superiority of waist-hip ratio and waist circumference over BMI for the prediction of incident HF.

HDL-cholesterol and the incidence of lung cancer in the Atherosclerosis Risk in Communities (ARIC) study.

SUMMARY: This study examined prospectively the association of baseline plasma HDL-cholesterol levels with incidence of lung cancer in 14,547 members of the Atherosclerosis Risk in Communities (ARIC) cohort. There were 259 cases of incident lung cancer identified during follow-up from 1987 through 2000. Results of this study indicated a relatively weak inverse association of HDL-cholesterol with lung cancer that was dependent on smoking status. The hazard ratio of lung cancer incidence in relation to low HDL-cholesterol, adjusted for race, gender, exercise, alcohol consumption, body mass index, triglycerides, age, and cigarette pack-years of smoking, was 1.45 (95% confidence interval 1.10, 1.92). This association was observed among former smokers (hazard ratio: 1.77, 95% confidence interval 1.05, 2.97), but not current smokers. The number of cases among never smokers in this study was too small (n=13) for meaningful interpretation of effect estimates. Excluding cases occurring within 5 years of baseline did not appreciably change the point estimates, suggesting lack of reverse causality. The modest association of low plasma HDL-cholesterol with greater incident lung cancer observed in this study is in agreement with existing case-control studies.

Metabolic syndrome and cardiovascular disease in older people: The cardiovascular health study.

OBJECTIVES: To assess the prospective association between metabolic syndrome (MetS) and cardiovascular disease (CVD) in older people and to evaluate the effect of lowering the threshold for impaired fasting glucose (IFG) on the prevalence of IFG and MetS and the risk of CVD. DESIGN: Prospective cohort study. SETTING: Four field centers in U.S. communities. PARTICIPANTS: Three thousand five hundred eighty-five subjects in the Cardiovascular Health Study free of diabetes mellitus and CVD at baseline (mean age 72, 62% female, 14% black). MEASUREMENTS: Baseline measures of MetS components and adjudicated incident CVD events. MetS (2001) was defined first using the original criteria from the Third Adult Treatment Panel Report of the National Cholesterol Education Program (> or =3 of the following: large waist circumference (women >88 cm, men >102 cm), elevated triglycerides (> or =1.70 mmol/L), low high-density lipoprotein cholesterol (men <1.04 mmol/L, women <1.30 mmol/L), elevated fasting glucose (6.1-6.9 mmol/L), and high blood pressure (> or =130/85 mmHg or self-reported use of medications for hypertension). Subjects were also classified according to the revised definition of the MetS (2005) that applies the lower threshold for fasting glucose (5.6-6.9 mmol/L). RESULTS: During follow-up (median 11 years), 818 coronary heart disease (CHD), 401 stroke, and 554 congestive heart failure (CHF) events occurred. Age- and race-adjusted hazard ratios (HRs) for CHD, stroke, and CHF were 1.30 (95% confidence interval (CI) = 1.07-1.57), 0.94 (95% CI = 0.73-1.21), and 1.40 (95% CI = 1.12-1.76) for women and 1.35 (95% CI = 1.10-1.66), 1.51 (95% CI = 1.08-2.12), and 1.47 (95% CI = 1.14-1.90) for men, respectively. Overall, women and men with MetS (2005) were 20% to 30% more likely to experience any CVD event than subjects without MetS (2005). Using the lower cut-point for IFG resulted in a near tripling in IFG prevalence (16% to 46%) and an additional 9% classified with MetS (2005) but HRs similar to those estimated from the original MetS (2001) criteria. High blood pressure was the component most strongly associated with incident CHD. CONCLUSION: Results from this study of an elderly, population-based cohort provide support for earlier investigations in primarily middle-aged populations that link the presence of MetS with the development of CVD and further underscore the importance of recognizing and treating its individual components, particularly high blood pressure.

The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study.

OBJECTIVE: To assess the magnitude of the association between the National Cholesterol Education Program's Third Adult Treatment Panel Report (ATP III) definition of the metabolic syndrome and cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: Cox regression was used to estimate the relative risk of incident coronary heart disease (CHD) and stroke among 12,089 black and white middle-aged individuals in the Atherosclerosis Risk in Communities (ARIC) study. RESULTS: The metabolic syndrome was present in approximately 23% of individuals without diabetes or prevalent CVD at baseline. Over an average of 11 years of follow-up, 879 incident CHD and 216 ischemic stroke events occurred. Among the components of the metabolic syndrome, elevated blood pressure and low levels of HDL cholesterol exhibited the strongest associations with CHD. Men and women with the metabolic syndrome were approximately 1.5 and 2 times more likely to develop CHD than control subjects after adjustment for age, smoking, LDL cholesterol, and race/ARIC center (sex interaction P < 0.03). Similar associations were found between the metabolic syndrome and incident ischemic stroke. Comparison of receiver operating characteristic curves indicated that the metabolic syndrome did not materially improve CHD risk prediction beyond the level achieved by the Framingham Risk Score (FRS). CONCLUSIONS: Individuals without diabetes or CVD, but with the metabolic syndrome, were at increased risk for long-term cardiovascular outcomes, although statistical models suggested that most of that risk was accounted for by the FRS. Nevertheless, identification of individuals with the metabolic syndrome may provide opportunities to intervene earlier in the development of shared disease pathways that predispose individuals to both CVD and diabetes.

Prevalence of coronary heart disease and carotid arterial thickening in patients with the metabolic syndrome (The ARIC Study).

We determined the prevalence of the metabolic syndrome (MS) with the criteria recommended by the National Cholesterol and Education Program, Adult Treatment Panel III report and estimated the magnitude of cross-sectional associations between the MS, coronary heart disease (CHD), and atherosclerosis in 14,502 black and white middle-age patients in the Atherosclerosis Risk in Communities Study. CHD was ascertained by standardized procedures and subclinical atherosclerosis was determined by measuring carotid intimal medial wall thickness using B-mode ultrasonography. The prevalence of MS was 30%, with substantial variation across race and gender subgroups. Among women but not among men, MS was significantly associated with increasing low-density lipoprotein cholesterol. CHD prevalence was 7.4% among those with the MS compared with 3.6% in comparison subjects (p <0.0001). After adjustment for established risk factors, subjects who had MS were 2 times more likely to have prevalent CHD than were those who did not have the syndrome. Among individuals free of CHD and stroke, after adjustment for age, gender, and race/center, the average intimal-medial wall thickness of carotid arteries was greater among those with versus those without MS (747 vs 704 mum, p <0.0001). Thus, MS was significantly associated with the presence of CHD and carotid intimal medial wall thickness. Identification of patients who have MS may provide opportunities to initiate CHD prevention strategies.