Under-representation of subgroups of the population in clinical trials has been and continues to be a problem despite goals of academia, industry, and government. Older adults are among the groups that are under-represented in trials of medications that they are likely to receive once marketing approval has been received. Recent legislation that mandates that clinical trial participants be representative of patient population has been passed and creates hope that greater numbers of older adults will be enrolled in clinical trials and that they will be representative of "typical" geriatric patients. However, there is the need for collection of current data on disease prevalences with granularity as to age, gender, and race as well as geriatric co-morbidities to assess the representativeness of clinical trial participants relative to patient populations. Consensus on definitions and collection of data relevant to geriatric patient populations are needed to evaluate effects of comorbidities, frailty, cognitive and physical function. There will also be a need for expansion of the geriatric research workforce, facilities for research both in academic centers but also in the community and long-term care facilities, and for engagement with and involvement of communities that have been traditionally under-represented to conduct clinical trials that enroll truly representative patient populations.

Recent cardiovascular prevention guidelines place a greater emphasis on randomized placebo-controlled trial data as the basis for recommendations. While such trial data are sparse for people over the age of 75 or 80 years, data demonstrate altered risk-benefit relationships in these older patients. Primary prevention strategy decisions should consider estimated life expectancy and overall function as well as cardiovascular event risks, magnitude and time to benefit or harm, potentially altered adverse effect profiles, and informed patient preferences. Data support treatment of systolic hypertension to reduce stroke, cardiovascular events, and dementia in older patients with at least a 2-year estimated lifespan with modifications in systolic blood pressure goals and a need for greater attention to non-cardiovascular side effects such as falls in the very old. Lowering of elevated cholesterol levels with HMG-CoA reductase inhibitors for primary prevention in people over the age of 75 years requires greater individual considerations, as benefits may not accrue for 3-5 years and there is the potential impact of adverse effects. There is a rationale for lipid-lowering treatment in the more highly functional older patient with cardiovascular (especially stroke) risk higher than side effect risks in the near term and with an estimated lifespan longer than the time to benefit. Aspirin has higher side effect risks and requires a longer time to achieve benefit. Trial data are lacking on exercise interventions, but multi-system benefits have been shown in older patients such that exercise should be part of a preventive regimen. Preventive therapy in the very old means considering not only medical issues of co-morbidities, polypharmacy, and altered risk-benefit relationship of medications but also adjusting goals and approaches across the older agespan in keeping with informed patient preferences.

Objectives

To determine the potential effect of substituting glomerular filtration rate (GFR) estimates for renal clearance estimated using the Cockcroft-Gault method (CrCL-CG) to calculate direct oral anticoagulant (DOAC) dosing.

Design

Simulation and retrospective data analysis.

Setting

Community, academic institution, nursing home.

Participants

Noninstitutionalized individuals aged 19 to 80 from the National Health and Nutrition Examination Survey (NHANES) (2011/12) (n = 4,687) and medically stable research participants aged 25 to 105 (n = 208).

Measurements

Age, height, weight, sex, race, serum creatinine, CrCL-CG, and GFR (according to the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations). Outcome measures were dosing errors if GFR were to be substituted for CrCL-CG.

Results

Renal clearance estimates according to all methods were highly correlated (P < .001), although at lower clearances, substitution of GFR estimates for CrCL-CG resulted in failure to recognize needs for dose reductions of rivaroxaban or edoxaban in 28% of NHANES subjects and 47% to 56% of research subjects. At a CrCL-CG of less than 30 mL/min, GFR estimates missed indicated dosage reductions for dabigatran in 18% to 21% of NHANES subjects and 57% to 86% of research subjects. Age and weight contributed to differences between renal clearance estimates (P < .001), but correction of GFR for body surface area (BSA) did not reduce dosing errors. At a CrCL-CG greater than 95 mL/min, edoxaban is not recommended, and GFR esimates misclassified 24% of NHANES and 39% of research subjects. Correction for BSA reduced misclassification to 7% for NHANES and 14% in research subjects.

Conclusion

Substitution of GFR estimates for estimated CrCl can lead to failure to recognize indications for reducing DOAC dose and potentially higher bleeding rates than in randomized trials.

Objectives

To determine the dose-response relationship between 25-hydroxyvitamin D (25(OH)D) and supplemental vitamin D3 in elderly nursing home residents.

Design

Randomized double-blind investigation.

Setting

Nursing home.

Participants

Of 81 women (n=51) and men (n=30) (mean age 87.4±8) enrolled, 72 completed the study.

Intervention

Sixteen weeks of oral vitamin D3 at 800, 2,000, or 4,000 IU/d or 50,000 IU/wk.

Measurements

The main outcome was 25(OH)D concentrations (tandem mass spectrometry) after 16 weeks. Free 25(OH)D and intact parathyroid hormone (iPTH) were also analyzed. Safety monitoring of calcium and estimated glomerular filtration rate was performed, and adherence and clinical status were measured.

Results

25(OH)D concentrations increased with dose (P<.001) and were higher with 50,000 IU/wk (P<.001) than other doses and with 4,000 IU/d than 800 or 2,000 IU/d, but 800 IU and 2,000 IU/d did not differ. One subject receiving 800 IU/d had concentrations less than 20 ng/mL. All subjects receiving more than 2000 IU/d had concentrations of 20 ng/mL and greater. Free 25(OH)D concentrations rose with total 25(OH) vitamin D. Total and free 25(OH)D were related to calcium concentrations; only free 25(OH)D was related to iPTH.

Conclusion

25(OH)D increased linearly with 800 to 4,000 IU/d and 50,000 IU/wk of vitamin D3, without a ceiling effect. Data suggest that some elderly adults will require more than 800 IU/d of vitamin D3 to ensure adequate vitamin D levels. Changes in 25(OH)D with vitamin D3 were related to starting concentrations (greatest with the lowest concentrations and unchanged with 800 and 2,000 IU/d if 20-40 ng/mL). Relationships between serum calcium and iPTH and free 25(OH)D suggest the potential for free 25(OH)D in defining optimal 25(OH)D concentrations.