Drugs & Aging

Statins for Primary Prevention in Those Aged 70 Years and Older: A Critical Review of Recent Cholesterol Guidelines Abstract The risk of atherosclerotic cardiovascular disease rises with age and remains the leading cause of death in older adults. Evidence for the use of statins for primary prevention in older adults is limited, despite the possibility that this population may derive significant clinical benefit given its increased cardiovascular risk. Until publication of the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the Management of Blood Cholesterol, and the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease, guidelines for statin prescription in older adults remained unchanged despite new evidence of possible benefit in older adults. In this review, we present key updates in the 2018 and 2019 guidelines and the evidence informing these updates. We compare the discordant recommendations of the seven major North American and European guidelines on cholesterol management released in the past 5 years and highlight gaps in the literature regarding primary prevention of cardiovascular disease in older adults. As most cardiovascular events in older adults are nonfatal, we ask how clinicians should weigh the risks and benefits of continuing a statin for primary prevention in older adults. We also reframe the concept of deprescribing of statins in the older population, using the Geriatrics 5Ms framework: Mind, Mobility, Medications, Multi-complexity, and what Matters Most to older adults. A recent call from the National Institute on Aging for a statin trial focusing on older adults extends from similar concerns.

Optimizing Drug Therapies in Patients with COPD in the US Nursing Home Setting Abstract Chronic obstructive pulmonary disease (COPD) can be a disabling disease, and the impact on older adults is particularly evident in the nursing home setting. Chronic obstructive pulmonary disease is present in about 20% of nursing home residents, most often in women, and accounts for significant healthcare utilization including acute care visits for exacerbations and pneumonia, as well as worsening heart disease and diabetes mellitus. The emphasis on hospital readmissions is particularly important in nursing homes where institutions have quality measures that have financial implications. Optimizing drug therapies in individuals with COPD involves choosing medications that not only improve symptoms, but also decrease the risk of exacerbations. Optimizing the treatment of comorbidities such as heart disease, infections, and diabetes that may affect COPD outcomes is also an important consideration. Depending on the nursing home setting and the patient, the options for optimizing COPD drug therapies may be limited owing to patient-related factors such as cognition and physical impairment or available resources, primarily reimbursement-related issues. Choosing the best drug therapy for COPD in older adults is limited by the difficulty in assessing respiratory symptoms using standardized assessment tools and potentially decreased inspiratory ability of frail individuals. Because of cognitive and physical impediments, ensuring optimal delivery of inhaled medications into the lungs has significant challenges. Long-acting bronchodilators, inhaled corticosteroids, and roflumilast decrease the risk of exacerbations, although inhaled corticosteroids should be used judiciously in this population because of the risk of pneumonia and oropharyngeal side effects. Treatment of COPD exacerbations should occur early and consideration should be made to the benefits and risks of systemic corticosteroids and antibiotics. Clinical research in the COPD population in nursing homes is clearly lacking, and ripe for discovery of effective management strategies.

Use of Cholinesterase Inhibitors in Non-Alzheimer's Dementias Abstract Non-Alzheimer's dementias constitute 30% of all dementias and present with major cognitive and behavioral disturbances. Cholinesterase inhibitors improve memory by increasing brain acetylcholine levels and are approved symptomatic therapies for Alzheimer's disease (AD). They have also been investigated in other types of dementias with potential cholinergic dysfunction. There is compelling evidence for a profound cholinergic deficit in Lewy Body dementia (LBD) and Parkinson's disease dementia (PDD), even to a greater extent than AD. However, this deficit is difficult to objectivize in vascular dementia (VaD) given the increased comorbidity with AD. Furthermore, there is minimal to no evidence for cholinergic loss in frontotemporal dementia (FTD). Although cholinesterase inhibitors showed significant improvement in cognitive, behavioral, and functional measures in both LBD and PDD clinical trials, only rivastigmine is approved for PDD, due to the heterogeneity of the scales used, the duration of trials, and the limited sample sizes impacting data interpretation. Similarly, the interpretation of findings in VaD trials are limited by the lack of pre-defined inclusion criteria for 'pure VaD' and the wide heterogeneity of patients enrolled with respect to location and extent of cerebrovascular disease. In FTD patients, cholinesterase inhibitors were mostly associated with worsening of cognitive and behavioral symptoms. In non-AD dementias, cholinesterase inhibitors were well tolerated, with increased reports of mild to moderate cholinergic side effects and a non-significant trend for increased cardio and cerebrovascular events with rivastigmine in VaD, justifying their cautious use on a case-by-case basis, especially when there is evidence for cholinergic deficit.

Going Beyond the Guidelines in Individualising the Use of Antihypertensive Drugs in Older Patients Abstract Hypertension is commonly diagnosed in older patients, with increasing cardiovascular (CV) risk as systolic blood pressure (BP) increases. Maximising CV risk reduction must be reconciled with minimising the risk of treatment-related harms and burden, especially among frail, multi-morbid and older old patients who have been excluded from most randomised trials. Contemporary clinical guidelines, based on such trials, differ in their recommendations as to threshold levels warranting treatment with antihypertensive drugs (AHDs) and target levels that should be achieved. In optimising AHD prescribing in older patients, we propose the following decision framework: decide therapeutic goals in accordance with patient characteristics and preferences; estimate absolute CV risk; measure and profile BP accurately in ways that account for lability in BP levels and minimise error in BP measurement; determine threshold and target BP levels likely to confer net benefit, taking into account age, co-morbidities, frailty and cognitive function; and consider situations that warrant AHD deprescribing on the basis of potential current or future harm. In applying this framework to older persons, and based on a review of relevant randomised trials and observational studies, individuals most likely to benefit from treating systolic BP to no less than 130 mmHg are those of any age who are fit and have high baseline systolic BP (≥ 160 mmHg); high CV risk, i.e. established CV disease or risk of CV events exceeding 20% at 10 years; previous stroke or transient ischaemic attack; heart failure; and stage 3–4 chronic kidney disease with proteinuria. Individuals most likely to be harmed from treating BP to target systolic < 140 mmHg are those who have no CV disease and aged over 80 years; moderate to severe frailty, cognitive impairment or functional limitations; labile BP and/or history of orthostatic hypotension, syncope and falls; or life expectancy < 12 months. Treatment should never be so intense as to reduce diastolic BP to < 60 mmHg in any older person. At a time when guidelines are calling for less conservative management of hypertension in all age groups, we contend that a more temperate approach, such as that offered here and based on the totality of available evidence, may assist in maximising net benefit in older patients.

Did Generic Clopidogrel Commercialization Affect Trends of ER Consultations and Hospitalizations in the Population Treated with Clopidogrel? Abstract Background Clopidogrel has been widely used to prevent atherothrombotic events. Since 2011, pharmacists have offered their patients the opportunity to switch to generic clopidogrel, an economic alternative. Whether bioequivalence of generic cardiovascular drugs translates into clinical equivalence at a population level remains unclear and needs to be further documented. Objective We aimed to evaluate the impact of generic clopidogrel commercialization on adverse events (AEs): hospitalizations or emergency room (ER) consultations. Methods This is an interrupted time series analysis using the Quebec Integrated Chronic Disease Surveillance System. We included all patients ≥ 66 years old who were users of the brand-name clopidogrel or a generic version (n = 6) 24 months before and up to 12 months after generics commercialization. Rates of AEs were computed, and periods before and after generics commercialization were analyzed by segmented regression models along with exploratory analyses (generic vs. brand name). Sensitivity analyses were also performed using stratification of the time series by (1) sex, (2) the number of prevalent cardiovascular comorbidities, and (3) socioeconomic status. Results Time series were constituted of 89,525 clopidogrel users (mean age 78 years, 45% women, 71% ischemic heart disease, 34% stroke). For all users, there was a mean rate of 157 AEs per 1000 user-months, stable trend before (−0.1% [95% confidence interval −0.3 to 0.1] and after (0.0% [− 0.5 to 0.6]) generics commercialization. In exploratory analyses, once generic clopidogrel versions were commercialized, rates of AEs were 19.2% (95% CI 11.7–26.7) higher for generic versus brand-name users. This difference persisted up to 1 year. Sensitivity analyses yielded similar results. Conclusions The population treated with clopidogrel had similar rates of hospitalizations or ER consultations before and after generics commercialization. However, differences in rates of hospitalizations or ER consultations between generic and brand-name clopidogrel users may represent a drug safety signal which remains to be validated. Using a different study design, permitting adjustment for potential confounders, could be useful in this regard.

Population Pharmacokinetic/Pharmacodynamic Modeling of O -Desmethyltramadol in Young and Elderly Healthy Volunteers Abstract Background Age-related changes in the concentration–effect relationship of (+)-O-desmethyl-tramadol [(+)-ODM], tramadol's active metabolite, are not documented in the elderly. Objective The objective of this study was to characterize, in elderly and young subjects, the (+)-ODM pharmacokinetic and pharmacodynamic relationship to examine the effect of age after single-dose administration of tramadol 200 mg extended-release tablets. Methods A population analysis of a double-blind, randomized, placebo-controlled, two-period cross-over study including 13 elderly (aged ≥75 years) subjects with mild renal insufficiency and 16 young (aged 18–40 years) subjects was conducted. For 48 h post-dose, blood samples were collected and pain tolerance thresholds measured using an electrically stimulated pain model. A pharmacokinetic/pharmacodynamic model incorporating a one-compartment pharmacokinetic model for (+)-ODM parameterized with first-order formation rate, clearance (CL/fm), volume of distribution (V/fm) and a sigmoid maximum effect (Emax) model incorporating baseline (E0) and placebo effect was used. Results Maximum plasma concentrations of (+)-ODM occurred later and plasma concentrations declined more slowly in the elderly than in young subjects. In the elderly, V/fm was 76% larger and CL/fm 16% slower. Baseline (E0) and sensitivity (C50) for pain tolerance were similar between young and elderly subjects. However, the Emax parameter was 2.5 times higher in the elderly and maximum possible treatment-related effect was 169 (135–221) in the young and 194 (149–252) in the elderly; that is, 15% higher in the elderly. Conclusions This exploratory analysis suggests that age-related differences exist in the distribution and elimination of (+)-ODM, including a 76% larger distribution outside the central compartment and 16% slower clearance of (+)-ODM. These pharmacokinetic changes are associated with a 15% higher maximum possible treatment-related effect and carry the potential for greater efficacy but also the potential for increased side effects at the same dose in elderly subjects. Clinicaltrials.gov identifier: NCT02329561.

Reducing Psychotropic Drug Use in Nursing Homes in Belgium: An Implementation Study for the Roll-Out of a Practice Improvement Initiative Abstract Background and Objective Psychotropic drug use is high in nursing homes in Belgium. A practice improvement initiative (including education, professional support and the transition towards person-centred care) achieved significant reductions in psychotropic drug use. The initiative outline was transcribed into a general intervention template, and consequently implemented in five nursing homes (in mixed locations and with a mixed character) in preparation for a future broader roll-out in Belgium. The impact of the intervention on the use of psychotropic drugs in these five nursing homes is reported in this paper. Methods The general intervention template was fitted into the individual nursing home setting. Education for the nursing home personnel on psychotropic drugs and non-pharmacological alternatives, as well as details for a transition to person-centred care was provided. Psychotropic drug use was recorded using a dynamic cohort study design with cross-sectional observations (November 2016–November 2017). Results At baseline, participants' (n = 677) mean age was 85.6 years (range 54–109 years), with 72.6% female. Mean medication intake was 8.5 (range 1–22), predominantly central nervous system drugs (Anatomic Therapeutic Chemical classification N, 88.8%). Long-term (> 3 months) psychotropic drug use (62.0%) and concomitant psychotropic drug use (31.5% taking two or more medications) were high. After 12 months, the prevalence of long-term psychotropic drug use decreased significantly (from 62.0 to 52.9%, p < 0.001), likewise the combined use of psychotropic drugs (from 31.5 to 24.0%, p = 0.001). The decrease in the prevalence of antidepressant and hypnosedative use was significant (respectively, from 32.2 to 23.4%, p < 0.001, and from 35.3 to 28.7%, p = 0.006) in contrast to antipsychotic use (from 17.1 to 15.9%, p = 0.522). Conclusions The stand-alone adaptation of the previously reported initiative using a general template was possible. This intervention resulted in a significant decrease in psychotropic drug use (predominantly hypnosedatives and antidepressants) among nursing home residents after 12 months.

Prasterone: A Review in Vulvovaginal Atrophy Abstract Vulvovaginal atrophy (VVA) is a progressive condition commonly seen in postmenopausal women. The cessation of ovarian estrogen secretion and a fall in serum levels of dehydroepiandrosterone (DHEA), the remaining source of estrogens and androgens, are thought to promote the development of VVA in this population. Intravaginal prasterone (Intrarosa®) is a synthetic form of DHEA indicated for the treatment of VVA in postmenopausal women presenting with moderate to severe symptoms in the EU; prasterone is also approved in the USA for the treatment of dyspareunia due to menopause. Approval for the treatment of VVA was based on the results of the phase III ERC-231 and -238 trials in which intravaginal prasterone 6.5 mg/day significantly improved the signs and symptoms of VVA (as assessed by the percentage of parabasal and superficial cells, vaginal pH and the severity of dyspareunia) compared with placebo. The beneficial effects of prasterone were also evident during 52 weeks' treatment in the phase III ERC-230 safety trial. Prasterone was generally well tolerated, with the most common treatment-emergent adverse event being application site discharge. During 52 weeks of treatment with prasterone, changes in serum concentrations of estrogenic and androgenic metabolites of DHEA increased from baseline but remained within the normal postmenopausal ranges. Thus, intravaginal prasterone is an effective and generally well-tolerated option for the treatment of VVA in postmenopausal women.

Systemic Treatment of Prostate Cancer in Elderly Patients: Current Role and Safety Considerations of Androgen-Targeting Strategies Abstract Prostate cancer commonly affects older men, with one out of five patients being diagnosed at 75 years or older. Elderly patients are more likely to have reduced performance and nutritional status, increased comorbidities, polypharmacy, and altered host-dependent pharmacokinetics and pharmacodynamics. Moreover, elderly patients are often underrepresented in clinical trials, mainly because of comorbidities and decline in performance status. The International Society of Geriatric Oncology recommends management of elderly patients according to fitness and personal preference, rather than chronological age. Since androgen signaling has a nodal role in prostate cancer progression, androgen-targeting agents remain the mainstay of systemic therapy for this disease. However, the potential benefit of these treatments may be compromised by toxicity, especially in elderly patients. Hence, management decisions require evidence-based consideration of both potential benefits and risks on an individualized basis. Furthermore, especially elderly patients should undergo geriatric screening and must be actively monitored during treatment to detect adverse events early and prevent complications. A personalized and vigilant approach could provide the elderly patient with the optimal benefits of existing and emerging prostate cancer treatments, while sparing them the risks of excessive toxicity and avoiding overtreatment.

Efficacy and Adverse Events of Immunotherapy with Checkpoint Inhibitors in Older Patients with Cancer Abstract The number of older patients with cancer is increasing as a result of the ageing of Western societies. Immune checkpoint inhibitors have improved cancer treatment and are associated with lower rates of treatment-related toxicity compared with chemotherapy in the general population. Nonetheless, immune checkpoint inhibitors have potentially serious immune-related adverse events, which might have a greater impact on older and more vulnerable patients and potentially influence treatment efficacy and quality of life. Previous clinical trials have shown no major increase in immune-related adverse events; however, older patients are underrepresented and relatively healthy in these trials. Observational studies suggest that older and more vulnerable patients may be at a higher risk of immune-related adverse events and early treatment discontinuation. Geriatric assessment could help identify older patients who will benefit from immune checkpoint inhibitors.

Alexandros Sfakianakis
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