Marie-Laure Laroche

Predicting and Preventing Adverse Drug Reactions in the Very Old

The size of the elderly population has been increasing steadily for several years. Individuals in this age group often have several concomitant diseases that require treatment with multiple medications. These drugs, for various reasons and especially as a consequence of potential accumulation, may be associated with adverse reactions. Of the numerous factors that can favour the occurrence of these adverse drug reactions, the most important are the pathophysiological consequences of aging, particularly as these apply to the very old.Although absorption of drugs is not usually reduced in the elderly, diffusion, distribution and particularly elimination decline with age. Furthermore, while hepatic metabolic function is fairly normal, renal function is usually markedly depressed in very old individuals, and this can translate into clinical consequences if it is not taken into account. This is why, before administration of any drug in the elderly, evaluation of glomerular filtration rate is essential. Validated estimations such as those obtained from the classical Cockcroft-Gault formula or from more recent methodologies are required.In addition to reductions in various organ functions, factors connected with very old age such as frailty, falls, abnormal sensitivity to medications and polypathology, all of which tend to be more common in the last years of life, all directly impact on adverse drug reaction occurrence.Given these characteristics of the elderly population, the best way to reduce the prevalence of adverse drug reactions in this group is to limit drug prescription to essential medications, make sure that use of prescribed agents is clearly explained to the patient, give drugs for as short a period as possible, and periodically re-evaluate all use of drugs in the elderly.

Impact of Hospitalisation in an Acute Medical Geriatric Unit on Potentially Inappropriate Medication Use

Background and objectivePotentially inappropriate medication use is a major safety issue in the elderly and may cause a substantial proportion of drug-related hospital admissions. Hospitalisation could result in a change in the quantity and type of drugs, but its effect on potentially inappropriate drug use is still unknown. The aim of this study was to estimate the potentially inappropriate medication prevalence in patients ≥70 years of age at admission to and at discharge from an acute medical geriatric unit, and to identify the factors associated with no longer being a potentially inappropriate drug user at hospital discharge.MethodsA prospective drug surveillance study was undertaken in 2018 elderly patients (≥70 years of age) admitted to an acute medical geriatric unit in Limoges University Hospital, France. Prescribing patterns were established at admission and at discharge. Potentially inappropriate medication use was evaluated according to a list derived from the Beers criteria and adapted to French practice. “To be no longer a potentially inappropriate drug user at discharge” was defined as using at least one potentially inappropriate medication at admission and not using it at discharge.ResultsThe numbers of drugs used at admission/discharge were 6.2 ± 3.1/5.4 ± 2.5. The prevalence of potentially inappropriate medication use decreased from 66% (95% CI 63.8, 68.0) at admission to 43.6% (95% CI 41.3, 45.9) at discharge. At discharge, 535 subjects were no longer potentially inappropriate medication users. Multivariate analysis showed that no longer being a potentially inappropriate medication user was associated with the number of drugs used (4–6 drugs vs ≤3 odds ratio [OR] 1.20; 95% CI 0.86, 1.68; 7–9 drugs vs ≤3 OR 1.37; 95% CI 0.97, 1.93; ≥10 drugs vs ≤3 OR 1.64; 95% CI 1.10, 2.44), age (80–89 years vs 70–79 years OR 1.38; 95% CI 1.03, 1.85; ≥90 years vs 70–79 years OR 1.69; 95% CI 1.22, 2.83), cerebral vasodilator use (OR 2.87; 95% CI 2.31, 3.57), analgesic use (OR 1.54; 95% CI 1.06, 2.25) and concomitant use of psychotropic drugs of the same therapeutic class (OR 1.94; 95% CI 1.29, 2.92).ConclusionHospitalisation in geriatric services results in a reduction in potentially inappropriate medication use. Improved pharmacological education of practitioners, especially with regard to drug adverse effects, is desirable to improve management of geriatric patients.

Trends of the potentially inappropriate medication consumption over 10 years in older adults in the East of France

To describe the trends of potentially inappropriate medication (PIM) use in older adults from 1995 to 2004 in the East of France, by using the 1997 Beers criteria and its French update, and to assess risk factors for this PIM use.

Potentially inappropriate drug use in older people: a nationwide comparison of different explicit criteria for population‐based estimates

AIMS The aim was to investigate the prevalence of potentially inappropriate medication use among older people in Sweden according to five different published sets of explicit criteria from Europe and the US. METHODS This was a nationwide cross-sectional, register-based study across the whole of Sweden in 2008. All individuals aged 65 years and older were included (n = 1 346 709, both community-dwelling and institutionalized persons). We applied all drug-specific criteria included in the 2012 Beers Criteria, the Laroches list, the PRISCUS list, the NORGEP criteria and the Swedish National Board of Health and Welfare criteria. The main outcome was the potentially inappropriate drug use according to each set of criteria, separately and combined. Multivariate logistic regression models were used to identify individual factors associated with the use of potentially inappropriate drugs. RESULTS The prevalence of potentially inappropriate medication use varied between the explicit criteria from 16% (NORGEP criteria) to 24% (2012 Beers criteria). Overall, 38% of the older people were exposed to potentially inappropriate drug use by at least one of the five sets of criteria. While controlling for other possible covariates, female gender, institutionalization and polypharmacy were systematically associated with inappropriate drug use, regardless of the set of explicit criteria we considered. CONCLUSION Although explicit criteria for inappropriate drug use among older people have been reported to be quite different in their content, they provide similar measures of the prevalence of potentially inappropriate drug use at the population level.

Quality of Phenobarbital Solid-dosage Forms in the Urban Community of Nouakchott (Mauritania)

Summary:  Purpose: Epilepsy is a major public‐health problem in Africa. The quality of available drugs is a limiting factor for an adequate management. The aim of this study was to describe the proportion of poor‐quality phenobarbital (PB) solid‐dosage forms and evaluate the factors associated with its quality in Nouakchott (Mauritania).

Adverse drug reactions in patients with Alzheimer's disease and related dementia in France: a national multicentre cross‐sectional study

To assess the prevalence of adverse drug reactions (ADRs) occurring in patients with Alzheimers disease (AD) or other dementia in France.

Adverse Drug Reactions Reported With Cholinesterase Inhibitors An Analysis of 16 Years of Individual Case Safety Reports From VigiBase

Background: No worldwide pharmacovigilance study evaluating the spectrum of adverse drug reactions (ADRs) induced by cholinesterase inhibitors (ChEI) in Alzheimer’s disease has been conducted since their emergence on the market. Objective: To describe ChEI related ADRs in Alzheimer’s disease (donepezil, rivastigmine, and galantamine) and characterize their seriousness as reported by national pharmacovigilance systems to VigiBase, a World Health Organization International Drug Monitoring Program database, between 1998 and 2013. Methods: All ChEI related reports, submitted to VigiBase between 1998 and 2013 from the five continents were extracted. Analyses were carried out for general, serious, and nonserious ADRs. Results: A total of 18 955 reports (43 753 ADRs) from 58 countries were reported: 60.1% in women; mean age 77.4 ± 9.1 years. Most reports originated from Europe (47.6%) and North America (40.4%). Rivastigmine and donepezil were involved in most reports (41.4% each). The most frequently reported ADRs were neuropsychiatric (31.4%), gastrointestinal (15.9%), general (11.9%), and cardiovascular (11.7%) disorders. During the 2006-2013 period, serious ADRs remained more often reported than nonserious ones; the most serious were neuropsychiatric (34.0%), general (14.0%), cardiovascular (12.1%), and gastrointestinal (11.6%) disorders. Medication errors were reported in 2.0% of serious cases. Death occurred in 2.3% of the reports. Conclusions: This international pharmacovigilance study highlights the ADR pattern induced by ChEIs. Neuropsychiatric events were the most frequently reported ADRs. Serious cardiovascular events were frequently reported, suggesting that their significance has probably been previously underestimated. Given the frailty of the patients and the frequent comedications, caution is advised before introducing a ChEI.

Are adverse drug reaction patterns different between romiplostim and eltrombopag? 2009–2013 French PharmacoVigilance assessment

BACKGROUND Romiplostim and eltrombopag, the two marketed thrombopoietin receptor agonists (TPO-RAs), have distinct binding sites and might have distinct pharmacodynamic mechanisms. The aim of this study was to compare their adverse drug reaction (ADR) patterns. METHODS We selected in the French PharmacoVigilance Database all ADRs associated with TPO-RAs from TPO-RA marketing until the 31st of December 2013. Medical charts were reviewed. We conducted disproportionality analyses comparing romiplostim exposure in the reports of a given ADR pattern (thrombosis, neurological, cutaneous, gastrointestinal or hematological) to romiplostim exposure in all other TPO-RA-related ADR reports. Reporting Odds Ratios (RORs) were adjusted for age and gender. We also compared the number of reports of a given ADR pattern per million daily defined doses (DDDs) dispensed in France during the study period. RESULTS We described 45 reports (53 ADRs) with romiplostim and 26 reports (37 ADRs) with eltrombopag. There were 19 venous thromboses. At least one other risk factor was present in 83.3% of the cases. Ten (55.6%) patients had been splenectomized previously. There were eight arterial thromboses. Another risk factor was noticed in all cases. There was no signal for an excess risk of thrombosis with romiplostim versus eltrombopag (ROR: 1.45, 95% CI [0.48-4.45]). There was a signal for a higher risk of gastrointestinal ADRs with eltrombopag (ROR: 30.28, 95% CI [3.23-383.86]) and of hematological ADRs with romiplostim (ROR: 14.36, 95% CI [1.73-119.08]). Dispensing data-adjusted comparisons led to similar results. CONCLUSIONS This study suggests different ADR patterns between romiplostim and eltrombopag.

Towards therapeutic drug monitoring of everolimus in cancer? Results of an exploratory study of exposure-effect relationship

Introduction: Therapeutic drug monitoring (TDM) of everolimus is not performed in oncology and no trough level (C0) target has been yet defined. The aim of this study was to determine everolimus C0 target for toxicity and efficacy. Materials and methods: Clinical, biological and radiologic data from 54 patients were collected. Toxicity event was defined by termination, temporary interruption and/or dose reduction of everolimus while efficacy was defined as progression‐free survival. C0 values were dichotomized by ROC curve analysis and the association between exposure and outcome was determined using Cox models for repeated events (toxicity) or Cox model censured at the first event (progression free survival). Results: Among the 42 patients (77.8%) with breast cancer, 10 (18.5%) kidney cancer and 2 (3.7%) neuroendocrine cancer, adverse events were reported in 75.9% of the patients (everolimus termination in 25.9% patients). C0 everolimus higher than 26.3 ng/mL (Sen = 0.38,Spe = 0.88) were associated with a 4‐fold increased risk of toxicity (HR = 4.12, IC95% = [1.48–11.5], p = 0.0067) whereas C0 lower than 11.9 ng/mL were associated with a 3‐fold increased risk of progression (HR = 3.2, IC95% = [1.33–7.81],p = 0.001). Discussion: Further studies are required to evaluate the everolimus C0 threshold proposed for toxicity (26.3 ng/mL) and for progression (11.9 ng/mL) especially with a large number of patients and more homogeneous types of cancer. However, these results are in favour of TDM for everolimus in oncology.

Frailty and Pain : two related conditions

Frailty is a multidimensional syndrome, involving functional, nutritional, biological and psychological aspects. This condition, defined as a decreased resistance to internal and external stressors, is predictive of adverse health outcomes, including disability and mortality. Importantly, the frailty syndrome is usually considered a reversible condition, thus amenable of specific preventive interventions. Persistent pain in older adults is very common and has multiple determinants. This symptom represents a determinant of accelerated aging. In the present paper, we discuss available evidence examining the association between these two conditions. Despite the high prevalence of these two conditions and their shared underlying mechanisms, our search only retrieved few relevant studies. Most of them reported a relationship between pain (or analgesics consumption) and different operational definitions of frailty. Pain may represent a relevant risk factor as well as a potential target for interventions against the frailty syndrome, but further studies are needed.