Current status of inclusion of older groups in evaluations of new medications: Gaps and implementation needs to fill them.

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.

Attitudes on participation in clinical drug trials: A nationally representative survey of older adults with multimorbidity.

BACKGROUND: Older adults with multimorbidity are under-represented in clinical drug trials. Their inclusion will not increase unless they are willing and able to participate. Data on motivators and barriers to participation in trials of new medications of older adults with multimorbidity are needed. METHODS: Cross-sectional internet and telephone survey of a nationally representative sample of adults ≥65 years with ≥3 chronic conditions (NORC University of Chicago Amerispeak Panel) conducted from March-April, 2023 to determine motivators and barriers to drug trial participation, described graphically and using statistics. RESULTS: Surveyed 1318 (1142 Internet, 176 phone) with mean age 72.3 ± 6.3 (SD), 52% women; race: 83% White, 10% Black or African American, 5% Hispanic or Latino, 1.1% Asian; 4.4 ± 1.9 chronic conditions (of 16 queried), taking 7.5 ± 3.3 medications. Barriers included fear of side effects (48%), taking too many medications (44%), placebo (44%), mobility (33%), bathroom needs (25%), hearing (19%), eyesight (15%), video visits (33%; higher in women, Black or African-American respondents, and those ≥80 years). Sixty-five percent would join all in-person trials, 49% would join all-video trials. Travel >1 h was difficult for 66%, most difficult for women. Trust was a concern in 25% of Black respondents. Caregiving responsibilities or lack of time were not obstacles. Participants were most likely to consider a drug trial for a problem they have (63%) versus prevention (44%) and if invited by a physician (80%) or University healthcare system (58%). Getting better care was ranked very important (79%) followed by helping others (57%). CONCLUSIONS: Major concerns of older patients with multimorbidity about participation in drug trials are potential side effects, taking too many medicines, and video visits. Physicians have the greatest influence on decisions and in-person visits are preferred. Proposed changes in trial design to increase enrollment of under-represented older adults may not align with patient-reported preferences.

Reasons for Nonadherence to the Direct Oral Anticoagulant Apixaban: A Cross-Sectional Survey of Atrial Fibrillation Patients.

Background: Nonadherence to direct oral anticoagulants to prevent stroke occurs in up to 40% of atrial fibrillation patients. Underlying reasons are poorly understood. Objectives: This study quantified patient-reported reasons for nonadherence and identified strategies to improve adherence. Methods: This is a cross-sectional survey of atrial fibrillation patients in 2 academic health systems who reported apixaban nonadherence. We examined patient-reported reasons for nonadherence and level of nonadherence (assessed by a validated 3-item adherence measure) using a multivariable logistic regression model. Results: Of 419 study patients, 41.5% were women. The mean age was 71.1 ± 10 years and mean CHA2DS2VASc score was 3.2 ± 1.6. About two-thirds had adherence scores ≥80 (mild nonadherence) and one-third scores <80 (poor adherence). In all groups, forgetfulness contributed to nonadherence. Attitudes/beliefs associated with adherence score <80 included: not believing apixaban was needed (odds ratio [OR]: 12.24 [95% CI: 2.25-66.47]); medication cost (OR: 3.97 [95% CI: 1.67-9.42]); and fear of severe bleeding (OR: 3.28 [95% CI: 1.20-8.96]). Strategies that patients with adherence scores <80 selected as helping "a great deal/a lot" to increase adherence included bloodwork to evaluate efficacy (56%), physician counseling about adherence (55%), and having a reversal agent (39%). Almost one-half of all patients did not disclose nonadherence to their providers. Conclusions: Patients may not disclose their nonadherence to prescribers, and attitudes related to apixaban nonadherence differ among patients with mild nonadherence versus poor adherence. While all patients may benefit from strategies to address forgetfulness, concerns related to the purpose of apixaban, cost, and bleeding risk may require special attention in those with poor adherence.

Participation of Older Adults in Clinical Trials for New Drug Applications and Biologics License Applications From 2010 Through 2019.

Importance: Older age may be accompanied by changes in the pharmacokinetics or pharmacodynamics or both of medications that can result in altered safety and efficacy profiles. Objective: To assess representation of older adults in clinical trials of new drug applications (NDAs) and biologics license applications (BLAs). Design, Setting, and Participants: This cross-sectional study analyzed US Food and Drug Administration (FDA) data for NDAs and BLAs approved from 2010 through 2019. Age distribution of clinical trial participants was compared with age distribution of the US population with the disease or disorder (prevalent population). Data were from adults enrolled in registration trials for depression, heart failure, insomnia, non-small cell lung cancer (NSCLC), nonvalvular atrial fibrillation (NVAF) stroke prevention, osteoporosis, and type 2 diabetes or adults sampled from US prevalent population in community-dwelling health data. Data were analyzed from November 2020 to February 2021. Exposures: Trial enrollment. Main Outcomes and Measures: Representativeness of trial populations was assessed by the participation to prevalence ratio (PPR) defined as the percentage of patients by age group among clinical trial participants to the percentage of patients by age group among US prevalent population. Results: Data from 166 clinical trials (229 558 participants) for 44 NDAs and BLAs were analyzed. The most consistent finding was the limited enrollment of the oldest age groups, namely those 75 years and above for type 2 diabetes and NSCLC, and 80 years and above for NVAF stroke prevention, insomnia, heart failure, and osteoporosis. Adults aged 60 to 74 years were enrolled in equal or greater proportion than the US prevalent population. Conclusions and Relevance: In this cross-sectional study, underrepresentation of the oldest adults existed during evaluation of new drugs and biologics, yet the older adults may represent significant proportions of the treatment population. Closing the representation gap between clinical trial enrollment and potential treatment populations is essential for safe and effective use of new drugs and biologics.

Polypharmacy in Older Heart Failure Patients: a Multidisciplinary Approach.

PURPOSE OF REVIEW: We provide a review of considerations when applying principles of optimal pharmacotherapy to older adults with heart failure (HF), an analysis on the pivotal clinical trials focusing on applicability to older adults, and multi-disciplinary strategies to optimize the health of HF patients with polypharmacy. RECENT FINDINGS: Polypharmacy is very common among patients with HF, due to medications for both HF and non-HF comorbidities. Definitions of polypharmacy were not developed specifically for older adults with HF and may need to be modified in order to meaningfully describe medication burden and promote appropriate medical therapy. This is because clinical practice guidelines for multi-drug HF regimens have unique considerations, given that they improve outcomes and symptoms of HF. Adults older than 65 years are well represented in contemporary clinical trials for HF with preserved ejection fraction (HFpEF) and guideline directed medical therapy (GDMT) for HF with reduced ejection fraction (HFrEF). While these trials did not have significant heterogeneity in safety or efficacy across a broad age spectrum, some may have limited representation of adults ≥ 80 years old, the sickest older adults, or those with decreased functional status. There is also a lack of data on the safety and efficacy of deprescribing HF medications, and deprescription in otherwise stable patients may lead to clinical destabilization or disease progression. There is therefore innate tension between the well-studied benefits of optimized HF therapy for older adults that must be weighed against the risks of polypharmacy and many unknowns that still exist. Given the strong evidence that optimized HF therapies confer symptomatic and mortality benefits for older adults, it is clear that polypharmacy in this context can be appropriate. A shift in paradigm is therefore needed when evaluating polypharmacy in patients with HF. Instead of assuming all polypharmacy is "good" or "bad," we propose a concerted move, using a multidisciplinary approach, to focus on the "appropriateness" of specific medications, in order to optimize HF medical therapy. Clinicians of all specialties caring for complex older adults with HF must consider goals of care, functional status, and new evidence-based therapies, in order to optimize this polypharmacy for older adults.

Apixaban Concentrations in Routine Clinical Care of Older Adults With Nonvalvular Atrial Fibrillation.

BACKGROUND: Direct-acting oral anticoagulants are first-line agents for prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF), but data are limited for the oldest patients, and with reduced dosing. OBJECTIVES: To determine steady-state apixaban peak and trough concentrations during routine care of older adults with NVAF, compare concentrations to clinical trial concentrations, and explore factors associated with concentrations. METHODS: A cross-sectional study of medically stable older adults with NVAF (≥75 years or ≥70 years if Black) receiving apixaban. Peak (2-4.4 hours post-dose) and trough (before next dose) concentrations were determined by anti-Xa activity calibrated chromogenic assay. Patient characteristics associated with concentrations were determined by multivariate modeling. RESULTS: The median age of patients (n = 115) was 80 (interquartile range: 77-84) years. The cohort comprised 46 women and 69 men; of which 98 are White, 11 Black, and 6 Asian. With 5 mg twice daily per labelling (n = 88), peak concentrations were higher in women: 248 ± 105 vs 174 ± 67 ng/mL in men (P < 0.001) and exceeded expected 95% range in 6 of 30 vs 0 of 55 men (P = 0.002). With 2.5 mg twice daily per label (n = 11), concentrations were <5 mg twice daily (peak: 136 ± 87 vs 201 ± 90 ng/mL, P = 0.026; trough: 65 ± 28 vs 109 ± 56 ng/mL, P < 0.001), but not different than 2.5 mg twice daily without reduction criteria (n = 13; peak: 132 ± 88; trough: 65 ± 31 ng/mL). Covariates associated with concentrations included sex, number of daily medications, and creatinine clearance. CONCLUSIONS: Older women had higher than expected peak apixaban concentrations, and 2.5 mg twice daily produced lower concentrations than standard dosing. Factors not currently included in dosing recommendations affected concentrations. The impact of apixaban concentrations on outcomes needs evaluation.

Roadmap to 2030 for Drug Evaluation in Older Adults.

Changes that accompany older age can alter the pharmacokinetics (PK), pharmacodynamics (PD), and likelihood of adverse effects (AEs) of a drug. However, older adults, especially the oldest or those with multiple chronic health conditions, polypharmacy, or frailty, are often under-represented in clinical trials of new drugs. Deficits in the current conduct of clinical evaluation of drugs for older adults and potential steps to fill those knowledge gaps are presented in this communication. The most important step is to increase clinical trial enrollment of older adults who are representative of the target treatment population. Unnecessary eligibility criteria should be eliminated. Physical and financial barriers to participation should be removed. Incentives could be created for inclusion of older adults. Enrollment goals should be established based on intended treatment indications, prevalence of the condition, and feasibility. Relevant clinical pharmacology data need to be obtained early enough to guide dosing and reduce risk for participation of older adults. Relevant PK and PD data as well as patient-centered outcomes should be measured during trials. Trial data should be analyzed for differences in PK, PD, effectiveness, and safety arising from differences in age or from the presence of conditions common in older adults. Postmarket evaluations with real-world evidence and drug labeling updates throughout the product lifecycle reflecting new knowledge are also needed. A comprehensive plan is needed to ensure adequate evaluation of the safety and effectiveness of drugs in older adults.

Anti-factor Xa activity assays of direct-acting oral anticoagulants during clinical care: An observational study.

BACKGROUND: Direct-acting oral anticoagulants (DOACs) are increasingly used to prevent and treat thromboembolism. Although measurement of DOAC concentrations is not currently recommended as part of routine patient care, measurement of DOAC concentrations with anti-factor Xa activity assays have recently become clinically available. OBJECTIVES: Our goal was to determine the clinical conditions under which DOAC concentration measurements are requested. MATERIALS AND METHODS: Retrospective electronic medical record analysis of indications for DOAC concentration measurements by anti-factor Xa activity assay at a single academic medical center from July 2015 through April 2020. RESULTS AND CONCLUSIONS: Ninety-one DOAC concentration measurements were made in 69 patients: 28 received apixaban and 41 received rivaroxaban. The most frequent indication for concentration measurement was drug exposure assessment (38/69; 55%) in patients with potentially altered pharmacokinetics (altered absorption or clearance), recurrent thromboembolic events, or possible medication nonadherence. Fourteen of 69 patients had repeated measurements during preoperative evaluation before emergent surgery; one-third of those with detectable levels upon presentation had repeated measurements until concentrations were undetectable. Levels were undetectable in 4 of 4 patients scheduled for elective surgery. Eleven of 69 patients had DOAC measurements in the setting of major bleeding; 5 of these 11 received a specific DOAC reversal agent. While most of the observed indications appear in clinical guidelines, altered absorption does not. Overall, clinicians are requesting DOAC concentration measurements to evaluate drug exposure in patients with conditions that might alter the absorption or clearance of the DOAC, to evaluate surgical bleeding risk, and in the setting of major bleeding.

Primary nonadherence to statin medications: Survey of patient perspectives.

Statin medications reduce cardiovascular events, but many patients never start taking their prescribed statin (primary nonadherence). Limited knowledge exists about the attitudes and beliefs of those with primary nonadherence. In this study, patients with primary nonadherence to statin medications (n = 173) completed a self-administered cross-sectional survey that assessed their attitudes and beliefs related to primary nonadherence and to potential motivators for statin use. Patients were recruited in 2019 from two academic health systems and nationwide internet advertisements. Only 49 of 173 (28.3%) patients with primary nonadherence reported having cardiovascular disease (CVD). Ninety-nine patients (57.2%) never filled their prescription, and 74 (42.8%) filled but never took any statin. Over half failed to initially inform their prescriber they might not take the statin. Patients strongly or somewhat agreed that they desired alternate treatment plans such as diet and/or exercise (n = 134; 77.4%) or natural remedies/dietary supplements (n = 125; 72.3%). Ninety-eight (56.6%) stronglyor somewhat worried about the possibility of statin dependence or addiction. Twenty-seven (15.6%) patients noted that they would not take a statin based solely on CVD risk estimates; 50 (28.9%) selected a CVD risk threshold of >20%; and 23 (13.3%) a threshold of >50% as motivating factors to take statins. Patients with primary nonadherence have attitudes about taking statins based on CVD risk that differ from scientific recommendations, may not tell providers about their hesitation to take statins, and likely prefer alternative initial approaches to cholesterol lowering. Early shared decision-making and assessment of patient attitudes about statins could potentially better align initial approaches for CVD risk reduction.

Perceptions of Patients with Primary Nonadherence to Statin Medications.

BACKGROUND: Despite emphasis on efforts to prevent cardiovascular disease (CVD), 13% to 34% of people never fill a prescribed statin (primary nonadherence). This study determined perceptions of adults with primary nonadherence to statins. METHODS: Ten focus groups were conducted with 61 adults reporting primary nonadherence to statins (93% without known CVD). Participants were recruited from an academic medical center and nationwide Internet advertisements. RESULTS: Major themes related to primary nonadherence were 1) desire to pursue alternatives before starting a statin (eg, diet and/or exercise, dietary supplements), 2) worry about risks and adverse effects of statins, 3) perceptions of good personal health (suggesting that a statin was not needed), and 4) doubt about the benefits of statins in the absence of disease. Additional themes included mistrust of the pharmaceutical industry, mistrust of prescribing providers, inadequate provider communication about statins, and negative prior experiences with medication. Although rare, a few patients said that high cholesterol does not require treatment if it is genetic. One third noted during focus group discussions that they did not communicate their decision not to take a statin to providers. CONCLUSIONS: Adults with primary nonadherence to statins describe seeking alternatives, avoiding perceived risks of statins, poor acceptance/understanding of CVD risk estimates, and doubts about the benefits of statins. Many do not disclose their decisions to providers, thus highlighting the need for provider awareness of the potential for primary nonadherence at the point of prescribing, and the need for future work to develop strategies to identify patients with potential primary nonadherence.

Prevalence and Knowledge of Potential Interactions Between Over-the-Counter Products and Apixaban.

BACKGROUND: Direct-acting oral anticoagulants (DOACs), such as apixaban, are the most commonly prescribed anticoagulants, with advantages in that they do not require routine monitoring. However, less frequent contact with healthcare professionals may contribute to poor patient knowledge about potential interactions between over-the-counter (OTC) products and DOACs. OBJECTIVE: Determine the prevalence of use of OTC products (OTC medications and dietary supplements) with potentially serious apixaban interactions and assess patient knowledge of potential interactions. DESIGN: Cross-sectional survey. SETTING: Academic-affiliated outpatient medical practices in northern and southern California. PARTICIPANTS: A total of 791 English- or Spanish-speaking patients prescribed apixaban. MEASUREMENTS: Use and knowledge of OTC medications and dietary supplements with potentially serious apixaban interactions. RESULTS: Almost all respondents (n = 771; 97.5%) reported OTC product use. Of respondents, 33% (n = 266) took at least one OTC product with potentially serious apixaban interactions daily/most days and 53 (6.7%) took multiple products (mean = 2.6 [SD = 2.6]). Aspirin was taken daily by 116 (14.7%; of which 75 [64.7%] also consumed other potentially interacting OTC products), and some days/as needed by an additional 82 (10.4%). Ibuprofen and naproxen were taken daily/most days by 14 (1.8%) and occasionally by 225 (28.5%). Dietary supplements with potentially serious interactions were taken daily/most days by 160 (20.2%). Approximately 66% of respondents were either uncertain or incorrect about the potential for increased bleeding from combining nonsteroidal anti-inflammatory drugs and apixaban. Less knowledge about OTC products with potentially serious interactions was associated with greater OTC product use (odds ratio = 0.54; 95% confidence interval = 0.35-0.85). CONCLUSION: Significant numbers of patients take OTC products (particularly dietary supplements) with potentially serious interactions with the DOAC apixaban and appear to lack knowledge about potentially harmful interactions. Interventions are needed to educate patients and healthcare providers about potential dangers of taking interacting OTC products in combination with apixaban, and data are needed on outcomes associated with concomitant apixaban-OTC product use. J Am Geriatr Soc 68:155-162, 2019.