Persistent High Long-term Excess Mortality After Elective AAA Repair Especially in Women: A Large Population-based Study.

OBJECTIVE: The aim of this time-trend analysis is to estimate long-term excess mortality and associated cardiovascular risk for abdominal aortic aneurysm (AAA) patients after elective repair while addressing the changes in AAA management and patient selection over time. BACKGROUND: Despite the intensification of endovascular aneurysm repair and cardiovascular risk management, Swedish population data suggest that AAA patients retain a persistently high long-term mortality after elective repair. The question is whether this reflects suboptimal treatment, a changing patient population over time, or a national phenomenon. METHODS: Nationwide time-trend analysis including 40,730 patients (87% men) following elective AAA repair between 1995 and 2017. Three timeframes were compared, each reflecting changes in the use of endovascular aneurysm repair and intensification of cardiovascular risk management. Relative survival analyses were used to estimate disease-specific excess mortality. Competing risk of death analysis evaluated the risk of cardiovascular versus noncardiovascular death. Sensitivity analysis evaluated the impact of changes in patient selection over time. RESULTS: Short-term excess mortality significantly improved over time. Long-term excess mortality remained high with a doubled mortality risk for women (relative excess risk=1.87, 95% CI: 1.73-2.02). Excess mortality did not differ between age categories. The risk of cardiovascular versus noncardiovascular death remained similar over time, with a higher risk of cardiovascular death for women. Changes in patient population (ie, older and more comorbid patients in the latter period) marginally impacted excess mortality (2%). CONCLUSIONS: Despite changes in AAA care, patients retain a high long-term excess mortality after elective repair with a persistent high cardiovascular mortality risk. In this, a clear sex - but no age - disparity stands out.

Association between prescription opioid use and unplanned intensive care unit admission and mortality in the adult population of the Netherlands: a registry study.

BACKGROUND: Opioid overdoses are increasing in the Netherlands, and there may be other harms associated with prescription opioid use. We investigated the relationship between prescription opioid use and unplanned ICU admission and death. METHODS: This is an analysis of linked government registries of the adult Dutch population (age ≥18 years) alive on January 1, 2018. The co-primary outcomes were ICU admission and death up to 1 year. Crude event rates and event-specific adjusted hazard rates (aHRs) with 95% confidence intervals (CIs) were calculated using multivariable analysis for people with and without exposure to an opioid prescription. RESULTS: We included 13 813 173 individuals, of whom 32 831 were admitted to the ICU and 152 259 died during the 1 year follow-up. Rates of ICU admission and death amongst people who reimbursed an opioid prescription were 5.87 and 62.2 per 1000 person-years, and rates of ICU admission and death in those without a prescription were 2.03 and 6.34, respectively. Exposed individuals had a higher rate of both ICU admission (aHR 2.53; 95% CI: 2.45-2.60) and death (aHR 7.11; 95% CI: 7.02-7.19) compared with unexposed individuals. Both outcomes were more frequent amongst prescription opioid users across a range of subgroups. CONCLUSIONS: The rate of ICU admission and death was higher amongst prescription opioid users than non-users in the full cohort and in subgroups. These findings represent an important public health concern.

Risk of drug-related upper gastrointestinal bleeding in the total population of the Netherlands: a time-trend analysis.

OBJECTIVE: Many prescribed and over-the-counter medications, for example, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with upper gastrointestinal bleeding (UGIB). Recently, a decrease in prescribing of NSAIDs was observed in the Netherlands, but whether a similar decreasing trend could be observed in the incidence of severe UGIB (either fatal or requiring hospitalisation), contingent on medication prescription, is unknown. DESIGN: We conducted a cohort study using Dutch national statistics on pharmacy claims, hospitalisation and mortality between 2013 and 2018. We explored the incidence of sex-specific and age-specific severe UGIB in four (sub)populations: (A) total population, (B) without a filled prescrption for NSAIDs, (C) without filled prescriptions for NSAIDs and antithrombotic agents, (D) without any risk factors for UGIB. RESULTS: The cumulative incidence of severe UGIB did not decrease throughout the study period, regardless of the subgroup analysis. In the total population, it was 199 per 100 000 inhabitants (95% CI 197 to 201) in 2013-2014 and 260 (95% CI 258 to 263) in 2017-2018. The absolute risk of severe UGIB was 50% lower in the subgroup B than in the full cohort. It decreased further by 50% in the subgroup D when compared with subgroup B. The risk of severe UGIB was 1.5-1.9 fold higher in young women than in young men; an indication of over-the-counter NSAIDs use being more prevalent in women than men in this age group. CONCLUSION: We found no evidence to support a relationship between reduced prescribing of NSAIDs and the incidence of severe UGIB in the Netherlands since 2013. The relationship was also not observed when we removed the effect of risk factors.

Opioid epidemic: lessons learned and updated recommendations for misuse involving prescription versus non-prescription opioids.

INTRODUCTION: In the past decades, the opioid crisis has heavily impacted parts of the US society and has been followed by an increase in the use of opioids worldwide. It is of paramount importance that we explore the origins of the US opioid epidemic to develop best practices to tackle the rising tide of opioid overdoses. AREAS COVERED: In this expert review, we discuss opioid (over)prescription, change in perception of pain, and false advertisement of opioid safety as the leading causes of the US opioid epidemic. Then, we review the evidence about opioid dependence and addiction potential and provide current knowledge about predictors of aberrant opioid-related behavior. Lastly, we discuss different approaches that were considered or undertaken to combat the rising tide of opioid-related deaths by regulatory bodies, pharmaceutical companies, and health-care professionals. For this expert review, we considered published articles relevant to the topic under investigation that we retrieved from Medline or Google scholar electronic database. EXPERT OPINION: The opioid epidemic is a dynamic process with many underlying mechanisms. Therefore, no single approach may be best suited to combat it. In our opinion, the best way forward is to employ multiple strategies to tackle different underlying mechanisms.

Comparison of Two Different Analgesic Prescription Strategies and Healthcare Systems: Slovenia vs. the Netherlands.

Background: Prescribing practice of pain medication is changing in the Netherlands; opioids are used more often instead of nonsteroidal anti-inflammatory drugs (NSAIDs), therefore we aimed to compare the use of pain medication with Slovenia which has stringent prescribing rules for strong opioids. Methods: We conducted a cohort study into national prescription databases of the Netherlands and Slovenia covering pharmacy claims between January 1, 2013 and December 31, 2019. In the analysis about 17 million Dutch and 2 million Slovenian residents were included. Findings: The use of opioids and NSAIDs was higher in Slovenia than in the Netherlands. More frequent use of opioids in Slovenia could be almost entirely explained by weak opioids (about 6% of the population), whereas they were prescribed 50% less frequently in the Netherlands. The opioid use has increased by about 20% in the Netherlands (4.85 and 6.00% of the population in 2013 and 2018, respectively), and the majority of this increase could be explained by strong opioids (4.05% in 2018), specifically, by oxycodone whose use increased by more than 2-fold between 2013 and 2019. In comparison, oxycodone was seldomly used in Slovenia (about 0.3% of the population received a prescription in a year). Interpretation: When medication use is controlled by stringent prescribing rules, like for strong opioids in Slovenia, the use is lower as compared to when such rules do not exist.

Causes and consequences of the opioid epidemic in the Netherlands: a population-based cohort study.

Over the past decade opioid use has risen globally. The causes and consequences of this increase, especially in Europe, are poorly understood. We conducted a population-based cohort study using national statistics on analgesics prescriptions, opioid poisoning hospital admissions and deaths in the Netherlands from 2013 to 2017. Pain prevalence and severity was determined by using results of 2014-2017 Health Interview Surveys. Between 2013 and 2017 the proportion of residents receiving opioid prescription rose from 4.9% to 6.0%, and the proportion of those receiving NSAIDs decreased from 15.5% to 13.7%. Self-reported pain prevalence and severity remained constant, as 44.7% of 5,119 respondents reported no pain-impeded activities-of-daily-living in 2014 (aRR, 1.00 [95% CI, 0.95-1.06] in 2017 vs 2014). Over the observation period, the incidence of opioid poisoning hospitalization and death increased from 8.6 to 12.9 per 100,000 inhabitants. The incidence of severe outcomes related to opioid use increased, as 3.9% of 1,343 hospitalized for opioid poisoning died in 2013 and 4.6% of 2,055 in 2017. We demonstrated that NSAIDs prescription decreased and opioid prescription increased in the Netherlands since 2013, without an increase in pain prevalence and severity. Consequently, the incidence of severe outcomes related to opioids increased.

Opioid Prescription Patterns and Risk Factors Associated With Opioid Use in the Netherlands.

Importance: An increase in opioid prescription has been observed in the Netherlands. It is vital to understand this increase and to identify risk factors for opioid prescription to ensure that health interventions remain appropriately targeted. Objectives: To determine the prevalence of opioid prescriptions and adverse events associated with opioids, and to identify risk factors associated with opioid prescription in the Dutch population. Design, Setting, and Participants: This cohort study used national statistics from the Netherlands from January 1, 2013, to December 31, 2017, including the full Dutch population of 16 779 575 people in 2013 and 17 081 507 people in 2017. Data from the Dutch Health Monitor surveys of 2012 and 2016 were also included. Databases were anonymized prior to analysis. All analyses were performed between December 2018 and February 2019. Exposure: Opioid prescription. Main Outcomes and Measures: The main outcomes were the dynamics of opioid prescriptions, hospital admissions for opioid overdose, and opioid overdose mortalities. The secondary outcome was risk factors associated with opioid prescription. Results: In 2013, 814 211 individuals (4.9% of the total population) received an opioid prescription. In 2017, 1 027 019 individuals (6.0% of the total population) received at least 1 opioid prescription (mean [SD] age, 59.3 [18.5] years; 613 203 [59.7%] women). The rate of hospital admissions for opioid overdose was 9.2 per 100 000 inhabitants in 2013 and 13.1 per 100 000 inhabitants in 2017 (relative risk, 1.43 [95% CI, 1.34-1.52]). Similarly, an increased risk of opioid overdose death was observed, from 0.83 per 100 000 inhabitants in 2013 to 1.2 per 100 000 inhabitants in 2017 (relative risk, 1.49 [95% CI, 1.20-1.85]). Based on data from the 2012 Dutch Health Monitor survey, risk factors associated with opioid prescription included being older than 65 years (odds ratio [OR], 4.20 [95% CI, 3.98-4.43]), having only a primary school education (OR, 3.62 [95% CI, 3.46-3.77]), being widowed (OR, 3.30 [95% CI, 3.13-3.49]), reporting always feeling symptoms of depression (OR, 3.77 [95% CI, 3.41-4.18]), and reporting poor or very poor physical health (OR, 10.40 [95% CI, 10.01-10.81]). Self-reported back pain (OR, 4.34 [95% CI, 4.23-4.46]) and rheumatoid arthritis or fibromyalgia (OR, 3.77 [95% CI, 3.65-3.90]) were also associated with opioid prescription. However, unemployment (OR, 1.05 [95% CI, 0.96-1.13]) was not associated with opioid prescription, and alcohol use disorder (OR, 0.76 [95% CI, 0.73-0.80]) was negatively associated with opioid prescription. Conclusions and Relevance: This study found that opioid prescriptions have increased in the Netherlands. Although the risk of adverse events is still relatively low, there is an urgent need to review pain management to prevent a further increase in opioid prescription.

MiR-148a the epigenetic regulator of bone homeostasis is increased in plasma of osteoporotic postmenopausal women.

BACKGROUND: Osteoporosis is a prevalent skeletal disorder characterized by reduced bone mineral density and microarchitectural deterioration of bone tissue, resulting in bone fragility and low-trauma fractures. Imaging techniques are routinely used to detect low bone mass; however, they are unable to identify deterioration of bone quality. Recently, microRNAs have emerged as regulators of bone remodelling and potentially also as a new class of sensitive biomarkers of bone health to aid in diagnosis and treatment monitoring of osteoporosis. METHODS: To identify new plasma-based biomarkers associated with osteoporosis we analyzed microRNAs isolated from plasma samples of 74 postmenopausal women divided into osteoporotic (N = 17) and control groups (N = 57). A prior microRNA screening was performed where a few showed promise for further analysis. Quantitative polymerase chain reaction was used to investigate differences in expression of let-7d-5p, let-7e-5p, miR-30d-5p, miR-30e-5p, miR-126-3p, miR-148a-3p, miR-199a-3p, miR-423-5p and miR-574-5p between the two groups. Furthermore, correlation analysis between microRNA expression levels and patient bone mineral density measurements and fracture risk assessment tool (FRAX) as well as trabecular bone scores were performed. RESULTS: Expression of miR-148a-3p was significantly higher (p = 0.042) in the osteoporotic patient group compared to the controls. In addition, we identified correlations between miR-126-3p (ρ = 0.253, p = 0.032) and 423-5p (ρ = -0.230, p = 0.049) and parameters of bone quality and quantity. CONCLUSION: The results from our study, together with the functional role of miR-148a-3p in bone suggest that this microRNA could be considered as a potential new plasma-based biomarker for pathological changes associated with osteoporosis.