Statin treatment is not associated with an increased risk of adrenal insufficiency in real-world setting.

Introduction: Statins could reduce the synthesis of steroid hormones, thereby could cause adrenal insufficiency. We investigated this risk in a large nationwide database. Methods: We conducted a nested case-control study using a cohort of individuals affiliated to the French health insurance system in 2010, ≥18y and without adrenal insufficiency history. Each case had a first event of adrenal insufficiency between 2015 and 2017 and was matched to up to ten controls on age, sex, and prior treatment with corticosteroids. Statin exposure was measured over the five years preceding the index date, considering a six-month censoring lag-time. Association was estimated using a conditional logistic regression adjusted for confounders included in a disease risk score. Analyses were stratified on age, sex and corticosteroid history of use. Results: 4 492 cases of adrenal insufficiency were compared with 44 798 controls (median age 66y, 58% women), of which 39% vs. 33% were exposed to statins, respectively. No association between statin use and adrenal insufficiency was found when adjusting the model for confounders (adjusted odds ratio 0.98; 95% confidence interval 0.90-1.05). These results were consistent regardless of the exposure definition and stratifications considered. Conclusion: Statin-related adrenal insufficiency risk, if any, seems to be very limited and does not compromise the benefit of statin treatment.

Trajectories of Benzodiazepine Use among Older Adults from a Concordance-with-Guidelines Perspective: A Nationwide Cohort Study.

BACKGROUND AND OBJECTIVE: Benzodiazepines (including zolpidem and zopiclone) are often associated with higher-than-recommended intake and durations of use, especially in older adults. The objective of this study was to characterize trajectories of benzodiazepine use according to recommended patterns in older adults, and to assess predictors of the risk of developing each of these trajectories. METHODS: Using the French Health Insurance database, we constituted a cohort of adults aged ≥ 65 years who initiated benzodiazepines in 2007 and were followed for up to 8 years. Concordance with benzodiazepine use guidelines was assessed on a quarterly basis according to a "concordance-with-guideline score" with values 1-5. Group-based trajectory modeling was then applied as implemented in the Proc Traj procedure in SAS to define guideline-concordant trajectories based on seven baseline patient-centered characteristics: sex, complementary health insurance coverage, treated alcohol and tobacco use disorder, polypharmacy, hospital stay, and registered chronic diseases. RESULTS: Among 5080 new users (64.1% women, median age 74 years), six trajectories of benzodiazepine use were identified. Three, representing 70% of users, were concordant with guidelines, whereas three implied non-concordant benzodiazepine use for part or all of the benzodiazepine use follow-up. Polymedicated patients were more prone to develop chronic non-guideline-concordant initially guideline-concordant use, whereas those with a history of long-term disease and hospitalization were more likely to develop chronic non-guideline-concordant use. The number of prescribers during the first quarter, number of daily defined doses, use of loperamide, and use of psychostimulants were associated with a higher risk of developing an initial and persistent non-guideline-concordant use. Treatment initiation by a psychiatrist, initial use of World Health Organization (WHO) step-2 opioids and non-benzodiazepine anxiolytics or sedatives were associated with a higher risk of late non-guideline-concordant use. CONCLUSIONS: Concordance with guidelines varied over time during benzodiazepine use in older adults. A third of these adults will hypothetically follow one of the identified non-guideline-concordant trajectories, consisting of initial and/or late non-guideline concordance. This was associated with modifiable and nonmodifiable factors that clinicians should be aware of for tailoring the monitoring of patients.

Antidepressants Drug Use during COVID-19 Waves in the Tuscan General Population: An Interrupted Time-Series Analysis.

In Italy, during the COVID-19 waves two lockdowns were implemented to prevent virus diffusion in the general population. Data on antidepressant (AD) use in these periods are still scarce. This study aimed at exploring the impact of COVID-19 lockdowns on prevalence and incidence of antidepressant drug use in the general population. A population-based study using the healthcare administrative database of Tuscany was performed. We selected a dynamic cohort of subjects with at least one ADs dispensing from 1 January 2018 to 27 December 2020. The weekly prevalence and incidence of drug use were estimated across different segments: pre-lockdown (1 January 2018-8 March 2020), first lockdown (9 March 2020-15 June 2020), post-first lockdown (16 June 2020-15 November 2020) and second lockdown (16 November 2020-27 December 2020). An interrupted time-series analysis was used to assess the effect of lockdowns on the observed outcomes. Compared to the pre-lockdown we observed an abrupt reduction of ADs incidence (Incidence-Ratio: 0.82; 95% Confidence-Intervals: 0.74-0.91) and a slight weekly decrease of prevalence (Prevalence-Ratio: 0.997; 0.996-0.999). During the post-first lockdown AD use increased, with higher incidence- and similar prevalence values compared with those expected in the absence of the outbreak. This pandemic has impacted AD drug use in the general population with potential rebound effects during the period between waves. This calls for future studies aimed at exploring the mid-long term effects of this phenomenon.

The risk of dementia in patients using psychotropic drugs: Antidepressants, mood stabilizers or antipsychotics.

OBJECTIVE: The risk of dementia associated with the use of psychotropic drugs is not fully understood. A nested case-control study was carried out to assess the risk of dementia broadly defined or Alzheimer's disease associated with antidepressants, mood stabilizers or antipsychotics. METHODS: A cohort was formed from healthcare claim databases including all patients aged 50 and over with a first dispensing of the psychotropic drugs concerned between 2006 and 2017. Patients who developed dementia over the study period were considered as cases. The association between drug exposure prior to a five-year lag time and diagnosis of dementia was assessed by conditional logistic regression models. RESULTS: No association was found between dementia, either broadly defined or Alzheimer disease, and antidepressant or mood stabilizers. Findings were conflicting with regard to antipsychotics. First- and second-generation antipsychotics (FGA and SGA) were not associated with Alzheimer disease. SGA treatments of more than 3 months were associated with a higher risk of dementia broadly defined than no use of antipsychotics (Odds ratio [OR] 2.00; 95%CI 1.06-3.79; p = 0.03). In a sensitivity analysis using a lag time of 3 years, ever use of SGA and SGA treatments of more than 3 months were associated with a higher risk of dementia broadly defined than no use of antipsychotics (OR 1.71; 1.10-2.67; p = 0.02 and OR 1.84; 1.03-3.32; p = 0.04, respectively). CONCLUSION: The association between antipsychotics and dementia should be further investigated to establish patients, specific drugs, and patterns of treatment at risk. Prescribers should remain cautious when prescribing them.

Chronic polypharmacy at all age: A population-based drug utilization study.

Polypharmacy is a growing concern often described only in older people by cumulating all drugs taken. We aimed to describe chronic polypharmacy in France, regardless of age. A cross-sectional descriptive study was performed using the 1/97th representative sample of the French health insurance nationwide database (EGB). All subjects alive on January 1, 2015, and covered by the French healthcare insurance were included, and their information collected until December 31, 2015, or date of death. Drug exposures were estimated from drug dispensing dates and treatment durations. Chronic uses of drug were defined as drugs used daily for more than 6 months. Chronic polypharmacy corresponded to the exposure to five chronic uses of drug or more. In 2015, information of 584 862 subjects was collected (mean age: 42.2 years). Prevalence of chronic polypharmacy was 5.6% and incidence 1.1%. Prevalence of chronic polypharmacy increased noticeably from 0.2% for subjects aged 18 to 40 years to a maximum of 29.2% for subjects aged 80 to 90 years and then decreased to 23.6% for subjects aged 90 years and more. Lipid-modifying agents were the most frequent drugs involved in chronic polypharmacy (10% of exposure). According to age, the most important differences between the younger and older people were found for cardiovascular drugs (43.5% vs. 45.7% of exposure, respectively) and nervous system drugs (13.7% vs. 11.5% of exposure, respectively). This population-based study showed increasing of chronic polypharmacy and evolution of chronic drug patterns with age.

Impact of COVID-19 Lockdown, during the Two Waves, on Drug Use and Emergency Department Access in People with Epilepsy: An Interrupted Time-Series Analysis.

BACKGROUND: In 2020, during the COVID-19 pandemic, Italy implemented two national lockdowns aimed at reducing virus transmission. We assessed whether these lockdowns affected anti-seizure medication (ASM) use and epilepsy-related access to emergency departments (ED) in the general population. METHODS: We performed a population-based study using the healthcare administrative database of Tuscany. We defined the weekly time series of prevalence and incidence of ASM, along with the incidence of epilepsy-related ED access from 1 January 2018 to 27 December 2020 in the general population. An interrupted time-series analysis was used to assess the effect of lockdowns on the observed outcomes. RESULTS: Compared to pre-lockdown, we observed a relevant reduction of ASM incidence (0.65; 95% Confidence Intervals: 0.59-0.72) and ED access (0.72; 0.64-0.82), and a slight decrease of ASM prevalence (0.95; 0.94-0.96). During the post-lockdown the ASM incidence reported higher values compared to pre-lockdown, whereas ASM prevalence and ED access remained lower. Results also indicate a lower impact of the second lockdown for both ASM prevalence (0.97; 0.96-0.98) and incidence (0.89; 0.80-0.99). CONCLUSION: The lockdowns implemented during the COVID-19 outbreaks significantly affected ASM use and epilepsy-related ED access. The potential consequences of these phenomenon are still unknown, although an increased incidence of epilepsy-related symptoms after the first lockdown has been observed. These findings emphasize the need of ensuring continuous care of epileptic patients in stressful conditions such as the COVID-19 pandemic.

The Burden of Potentially Inappropriate Medications in Chronic Polypharmacy.

We aimed to describe the burden represented by potentially inappropriate medications (PIMs) in chronic polypharmacy in France. We conducted a nationwide cross-sectional study using data from the French National Insurance databases. The study period was from 1 January 2016 to 31 December 2016. Chronic drug use was defined as uninterrupted daily use lasting ≥6 months. Chronic polypharmacy was defined as the chronic use of ≥5 medications, and chronic hyperpolypharmacy as the chronic use of ≥10 medications. For individuals aged ≥65 (older adults), PIMs were defined according to the Beers and Laroche lists, and for individuals aged 45-64 years (middle-aged) PIMs were defined according to the PROMPT (Prescribing Optimally in Middle-aged People's Treatments) list. Among individuals with chronic polypharmacy, 4009 (46.2%) middle-aged and 18,036 (64.8%) older adults had at least one chronic PIM. Among individuals with chronic hyperpolypharmacy, these figures were, respectively, 570 (75.0%) and 2544 (88.7%). The most frequent chronic PIM were proton pump inhibitors (43.4% of older adults with chronic polypharmacy), short-acting benzodiazepines (older adults: 13.7%; middle-aged: 16.1%), hypnotics (6.1%; 7.4%), and long-acting sulfonylureas (3.9%; 12.3%). The burden of chronic PIM appeared to be very high in our study, concerning almost half of middle-aged adults and two-thirds of older adults with chronic polypharmacy. Deprescribing interventions in polypharmacy should primarily target proton pump inhibitors and hypnotics.

Primary Care of Opioid use Disorder: The End of "the French Model"?

BACKGROUND: In France, most patients with opioid use disorder (OUD) have been treated by buprenorphine, prescribed by general practitioners (GP) in private practice since 1996. This has contributed to building a 'French model' facilitating access to treatment based on the involvement of GPs in buprenorphine prescription. OBJECTIVES: Our study aimed to assess whether the involvement of primary care in OUD management has changed lately. MATERIALS AND METHODS: Using data from the French National Health Insurance database, we conducted a yearly repeated cross-sectional study (2009-2015) and described proportion of opioid maintenance treatment (OMT)-prescribing GPs and OMT-dispensing community pharmacies (CP); and number of patients by GP or CP. RESULTS: Whereas the number of buprenorphine-prescribing GPs in private practice remained quite stable (decrease of 3%), a substantial decrease in buprenorphine initial prescribers among private GPs was observed. In 2009, 10.3% of private GPs (6,297 from 61,301 French private GPs) prescribed buprenorphine for the initiation of a treatment, whereas they were 5.7% (n = 3,539 from 62,071 private GPs) in 2015 (43.8% decrease). GPs issuing initial prescriptions of buprenorphine tended to care for a higher number of patients treated by buprenorphine (14.6 ± 27.1 patients in 2009 to 16.0 ± 35.4 patients in 2015). The number of CPs dispensing buprenorphine remained quite stable (decrease of 2%), while there was a 7.5% decrease in the total number of French CPs across the study period. CONCLUSIONS: Our results suggest that primary care providers seem less engaged in buprenorphine initiation in OUD patients, while CPs have not modified their involvement towards these patients.

Risk of Intracranial Aneurysm and Dissection and Fluoroquinolone Use: A Case-Time-Control Study.

Background and Purpose- Fluoroquinolone use is associated with an increased risk of aortic aneurysm and dissection. We investigated this risk of arterial wall injury on intracranial arteries, given the similar pathophysiological mechanisms for aneurysm and dissection in both types of arteries. Methods- A case-time-control study was conducted using French National Insurance databases covering >60 million inhabitants. Cases were aged ≥18 years with first ruptured intracranial aneurysm and dissection between 2010 and 2015. For each case, fluoroquinolone use was compared between the exposure-risk window (day 30-day 1 before the outcome) and matched control windows (day 120-day 91, day 150-day 121, and day 180-day 151) and adjusted for time-varying confounders; potential time-trend for exposure was controlled using an age- and sex-matched reference group. Amoxicillin use was studied similarly for indication bias controlling. The potential excess of risk conveyed by fluoroquinolones was assessed by the ratio of OR for fluoroquinolones to that for amoxicillin. Results- Of the 7443 identified cases, 75 had been exposed to fluoroquinolones in the prior 180 days, including 16 in the 30-day at-risk window (385/97 cases exposed to amoxicillin, respectively). The adjusted OR for fluoroquinolones was 1.26 (95%CI, 0.65-2.41) and that for amoxicillin of 1.36 (95% CI, 1.05-1.78). Ratio of OR for fluoroquinolones to that for amoxicillin was estimated at 0.92 (95% CI, 0.46-1.86). Result was similar when extending outcome definition to unruptured events (ratio of OR for fluoroquinolones to that for amoxicillin, 0.97 [95% CI, 0.61-1.53]). Conclusions- This study did not evidence an excess of risk of intracranial aneurysm or dissection with fluoroquinolone use.

Polypharmacy: A general review of definitions, descriptions and determinants.

Polypharmacy is considered as the administration of many drugs. It is a major public health concern, which is growing worldwide. The identification of polypharmacy relies on drug count on a given time window. Polypharmacy exists if this count exceeds a predefined threshold. Although there is no consensus among scientists, five is the most frequently used number. Depending on the time-windows, polypharmacy can be qualified as simultaneous, cumulative, or continuous. Drugs can be selected according to the duration or the recurrence of their use thereby introducing the concept of chronic polypharmacy. This general review aimed to compile data from the literature regarding descriptions and determinants of polypharmacy, according to used definitions and studied populations. The prevalence of polypharmacy varied according to the definition used (from 4% to 57%). It was high in elderly people but was also non negligible in younger subjects such as middle aged. Cardiovascular, digestive and metabolism drugs were among the most frequent drugs involved in polypharmacy. The determinants of polypharmacy included factors linked to the patient (sociodemographic parameters such as age, sex, income, and place of residence, ethnicity, behaviour), factors linked to the disease (certain diseases such as cardiovascular or metabolic disease, multiple comorbidity status), as well as factors linked to the healthcare system or to the physician. Finally, to date, little data is available regarding polypharmacy appropriateness, although these data are needed to have clinically important information beyond a quantitative estimation. Further research is warranted to fill this gap.

Insufficient therapeutic management of hypertensive patients with renal failure in France.

BACKGROUND: Hypertension is both the cause and consequence of chronic renal failure (CRF). The prevalence of CRF, which itself is a cardiovascular risk factor, is not well known in France. AIMS: To estimate the prevalence of renal dysfunction among hypertensive patients who were seen by general practitioners (GP); to assess the drug management of hypertension in these patients according to their renal status. METHODS: A transversal observational study among patients of both genders aged 18 or more, with arterial blood pressure greater than 130/80 mmHg (i.e., over CRF-recommended blood pressure) or under antihypertensive drugs who were recruited in France by GP. RESULTS: Among the 2315 included patients, 1908 could be analyzed for their renal function. Of these, 70.5% had an estimated glomerular filtration rate (GFR) of 89 ml/min per 1.73 m(2) or lower. One third of these patients (31.4%) were suffering from renal failure (GFR