Long versus short-term opioid therapy for fibromyalgia syndrome and risk of depression, sleep disorders and suicidal ideation: a population-based, propensity-weighted cohort study.

OBJECTIVE: Fibromyalgia syndrome (FMS) is characterised by widespread pain and is associated with mood disorders such as depression as well as poor sleep quality. These in turn have been linked to increased risk of suicidal ideation. Clinical guidelines generally do not recommended opioids in FMS, but they are routinely prescribed to a considerable proportion of FMS patients. We assessed the association of long-term opioid prescription for FMS with risk of depression, sleep disorders and suicidal ideation, when compared with short-term opioid use. METHODS: Retrospective cohort study combing several population-wide databases covering a population of five million inhabitants, including all adults who received an initial opioid prescription from 2014 to 2018 specifically prescribed for FMS. We examined the occurrence of depression, sleep disorders or suicidal ideation outcomes in patients with an initial long-term opioid prescription (>90 days) versus those who received a short-term treatment (<29 days). We employed multivariable Cox regression modelling and inverse probability of treatment weighting based on propensity scores and we performed several sensitivity analyses. RESULTS: 10 334 patients initiated short-term (8309, 80.40%) or long-term (2025, 19.60%) opioids for FMS. In main adjusted analyses, long-term opioid use was associated with an increased risk for depression (HR: 1.58, 95% CI 1.29 to 1.95) and sleep disorder (HR: 1.30, 95% CI 1.09 to 1.55) but not with suicidal ideation (HR: 1.59, 95% CI 0.96 to 2.62). In models assessing outcomes since day 90, an increased risk for suicidal ideation was observed (HR: 1.76, 95% CI 1.05 to 2.98). CONCLUSION: These findings suggest that continued opioid use for 90 days or more may aggravate depression and sleep problems in patients with FMS when compared with patterns of short-term treatment.

Metadata for Data dIscoverability aNd Study rEplicability in obseRVAtional Studies (MINERVA): Development and Pilot of a Metadata List and Catalogue in Europe.

PURPOSE: Metadata for data dIscoverability aNd study rEplicability in obseRVAtional studies (MINERVA), a European Medicines Agency-funded project (EUPAS39322), defined a set of metadata to describe real-world data sources (RWDSs) and piloted metadata collection in a prototype catalogue to assist investigators from data source discoverability through study conduct. METHODS: A list of metadata was created from a review of existing metadata catalogues and recommendations, structured interviews, a stakeholder survey, and a technical workshop. The prototype was designed to comply with the FAIR principles (findable, accessible, interoperable, reusable), using MOLGENIS software. Metadata collection was piloted by 15 data access partners (DAPs) from across Europe. RESULTS: A total of 442 metadata variables were defined in six domains: institutions (organizations connected to a data source); data banks (data collections sustained by an organization); data sources (collections of linkable data banks covering a common underlying population); studies; networks (of institutions); and common data models (CDMs). A total of 26 institutions were recorded in the prototype. Each DAP populated the metadata of one data source and its selected data banks. The number of data banks varied by data source; the most common data banks were hospital administrative records and pharmacy dispensation records (10 data sources each). Quantitative metadata were successfully extracted from three data sources conforming to different CDMs and entered into the prototype. CONCLUSIONS: A metadata list was finalized, a prototype was successfully populated, and a good practice guide was developed. Setting up and maintaining a metadata catalogue on RWDSs will require substantial effort to support discoverability of data sources and reproducibility of studies in Europe.

Long-Term Effect of Home Blood Pressure Self-Monitoring Plus Medication Self-Titration for Patients With Hypertension: A Secondary Analysis of the ADAMPA Randomized Clinical Trial.

Importance: Patient empowerment through pharmacologic self-management is a common strategy for some chronic diseases such as diabetes, but it is rarely used for controlling blood pressure (BP). Several trials have shown its potential for reducing BP in the short term, but evidence in the longer term is scarce. Objective: To evaluate the longer-term effectiveness of BP self-monitoring plus self-titration of antihypertensive medication vs usual care for patients with poorly controlled hypertension, with passive follow-up and primary-care nursing involvement. Design, Setting, and Participants: The ADAMPA (Impact of Self-Monitoring of Blood Pressure and Self-Titration of Medication in the Control of Hypertension) study was a randomized, unblinded clinical trial with 2 parallel arms conducted in Valencia, Spain. Included participants were patients 40 years or older, with systolic BP (SBP) over 145 mm Hg and/or diastolic BP (DBP) over 90 mm Hg, recruited from July 21, 2017, to June 30, 2018 (study completion, August 25, 2020). Statistical analysis was conducted on an intention-to-treat basis from August 2022 to February 2024. Interventions: Participants were randomized 1:1 to usual care vs an individualized, prearranged plan based on BP self-monitoring plus medication self-titration. Main Outcomes and Measures: The main outome was the adjusted mean difference (AMD) in SBP between groups at 24 months of follow-up. Secondary outcomes were the AMD in DBP between groups at 24 months of follow-up, proportion of patients reaching the BP target (SBP <140 mm Hg and DBP <90 mm Hg), change in behaviors, quality of life, health service use, and adverse events. Results: Among 312 patients included in main trial, data on BP measurements at 24 months were available for 219 patients (111 in the intervention group and 108 in the control group). The mean (SD) age was 64.3 (10.1) years, and 120 patients (54.8%) were female; the mean (SD) SBP was 155.6 (13.1) mm Hg, and the mean (SD) diastolic BP was 90.8 (7.7) mm Hg. The median follow-up was 23.8 months (IQR, 19.8-24.5 months). The AMD in SBP at the end of follow-up was -3.4 mm Hg (95% CI, -4.7 to -2.1 mm Hg; P < .001), and the AMD in DBP was -2.5 mm Hg (95% CI, -3.5 to -1.6 mm Hg; P < .001). Subgroup analysis for the main outcome showed consistent results. Sensitivity analyses confirmed the robustness of the main findings. No differences were observed between groups in behaviors, quality of life, use of health services, or adverse events. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, BP self-monitoring plus self-titration of antihypertensive medication based on an individualized prearranged plan used in primary care reduced BP in the longer term with passive follow-up compared with usual care, without increasing health care use or adverse events. These results suggest that simple, inexpensive, and easy-to-implement self-management interventions have the potential to improve the long-term control of hypertension in routine clinical practice. Trial Registration: ClinicalTrials.gov Identifier: NCT03242785.

COVID-19 and pregnancy: A European study on pre- and post-infection medication use.

PURPOSE: The COVID-19 pandemic has impacted medication needs and prescribing practices, including those affecting pregnant women. Our goal was to investigate patterns of medication use among pregnant women with COVID-19, focusing on variations by trimester of infection and location. METHODS: We conducted an observational study using six electronic healthcare databases from six European regions (Aragon/Spain; France; Norway; Tuscany, Italy; Valencia/Spain; and Wales/UK). The prevalence of primary care prescribing or dispensing was compared in the 30-day periods before and after a positive COVID-19 test or diagnosis. RESULTS: The study included 294,126 pregnant women, of whom 8943 (3.0%) tested positive for, or were diagnosed with, COVID-19 during their pregnancy. A significantly higher use of antithrombotic medications was observed particularly after COVID-19 infection in the second and third trimesters. The highest increase was observed in the Valencia region where use of antithrombotic medications in the third trimester increased from 3.8% before COVID-19 to 61.9% after the infection. Increases in other countries were lower; for example, in Norway, the prevalence of antithrombotic medication use changed from around 1-2% before to around 6% after COVID-19 in the third trimester. Smaller and less consistent increases were observed in the use of other drug classes, such as antimicrobials and systemic corticosteroids. CONCLUSION: Our findings highlight the substantial impact of COVID-19 on primary care medication use among pregnant women, with a marked increase in the use of antithrombotic medications post-COVID-19. These results underscore the need for further research to understand the broader implications of these patterns on maternal and neonatal/fetal health outcomes.

Impact of the 2018 revised Pregnancy Prevention Programme by the European Medicines Agency on the use of oral retinoids in females of childbearing age in Denmark, Italy, Netherlands, and Spain: an interrupted time series analysis.

Background: In March 2018, the European pregnancy prevention programme for oral retinoids was updated as part of risk minimisation measures (RMM), emphasising their contraindication in pregnant women. Objective: To measure the impact of the 2018 revision of the RMMs in Europe by assessing the utilisation patterns of isotretinoin, alitretinoin and acitretin, contraceptive measures, pregnancy testing, discontinuation, and pregnancy occurrence concomitantly with a retinoid prescription. Methods: An interrupted time series (ITS) analysis to compare level and trend changes after the risk minimisation measures implementation was conducted on a cohort of females of childbearing age (12-55 years of age) from January 2010 to December 2020, derived from six electronic health data sources in four countries: Denmark, Netherlands, Spain, and Italy. Monthly utilisation figures (incidence rates [IR], prevalence rates [PR] and proportions) of oral retinoids were calculated, as well as discontinuation rates, contraception coverage, pregnancy testing, and rates of exposed pregnancies to oral retinoids, before and after the 2018 RMMs. Results: From 10,714,182 females of child-bearing age, 88,992 used an oral retinoid at any point during the study period (mean age 18.9-22.2 years old). We found non-significant level and trend changes in incidence or prevalence of retinoid use in females of child-bearing age after the 2018 RMMs. The reason of discontinuation was unknown in >95% of cases. Contraception use showed a significant increase trend in Spain; for other databases this information was limited. Pregnancy testing was hardly recorded thus was not possible to model ITS analyses. After the 2018 RMM, rates of pregnancy occurrence during retinoid use, and start of a retinoid during a pregnancy varied from 0.0 to 0.4, and from 0.2 to 0.8, respectively. Conclusion: This study shows a limited impact of the 2018 RMMs on oral retinoids utilisation patterns among females of child-bearing age in four European countries. Pregnancies still occur during retinoid use, and oral retinoids are still prescribed to pregnant women. Contraception and pregnancy testing information was limited in most databases. Regulators, policymakers, prescribers, and researchers must rethink implementation strategies to avoid any pregnancy becoming temporarily related to retinoid use.

Initial opioid prescription characteristics and risk of opioid misuse, poisoning and dependence: retrospective cohort study.

OBJECTIVE: To identify individual and initial prescription-related factors associated with an increased risk for opioid-related misuse, poisoning and dependence (MPD) in patients with non-cancer pain. METHODS: Cohort study linking several databases covering 5 million inhabitants of the region of Valencia, Spain, including all adults initiating prescription opioids in the period 2012-2018. To ascertain the association between the characteristics of the initial prescription choice and the risk of opioid MPD, we used shared frailty Cox regression models. We additionally considered death as a competing risk in sensitivity analyses. RESULTS: 958 019 patients initiated opioid prescription from 2012 to 2018, of which 0.13% experienced MPD. Most patients were prescribed tramadol as initial opioid (76.7%) followed by codeine (16.3%), long-acting opioids (6.7%), short-acting opioids (0.2%) and ultrafast opioids (0.1%). Initiation with ultrafast (HR 7.2; 95% CI 4.1 to 12.6), short-acting (HR 4.8; 95% CI 2.3 to 10.2) and long-acting opioids (HR 1.5; 95% CI 1.2 to 1.9) were associated with a higher risk of MPD when compared with tramadol. Initial prescriptions covering 4-7 days (HR 1.3; 95% CI 1.0 to 1.8), 8-14 days (HR 1.4; 95% CI 1.0 to 1.9), 15-30 days (HR 1.7; 95% CI 1.2 to 2.3) and more than one a month (HR 1.8; 95% CI 1.3 to 2.5) were associated with more MPD risk than initial prescriptions for 1-3 days. Treatments with >120 daily morphine milligram equivalents (MME) increased MPD risk (vs <50 MME, HR 1.6; 95% CI 1.1 to 2.2). Main individual factors associated with increased risk of MPD risk were male sex (HR 2.4; 95% CI 2.1 to 2.7), younger age (when compared with patients aged 18-44 years, patients aged 45-64 years, HR 0.4; 95% CI 0.4 to 0.5; patients aged 65-74 years, HR 0.4; 95% CI 0.3 to 0.5 and patients aged 75 years old and over, HR 0.7; 95% CI 0.6 to 0.8), lack of economic resources (2.1; 95% CI 1.8 to 2.5) and registered misuse of alcohol (2.9; 95% CI 2.4 to 3.5). Sensitivity analyses yielded overall comparable results. CONCLUSIONS: Our study identifies riskier patterns of opioid prescription initiation for non-cancer indications, as well as patient subgroups with higher risk of misuse, poisoning and dependence.

Home Blood Pressure Self-monitoring plus Self-titration of Antihypertensive Medication for Poorly Controlled Hypertension in Primary Care: the ADAMPA Randomized Clinical Trial.

BACKGROUND: Patient empowerment through pharmacological self-management is a common strategy in some chronic diseases such as diabetes, but it is rarely used for controlling blood pressure. OBJECTIVE: This study aimed to assess self-monitoring plus self-titration of antihypertensive medication versus usual care for reducing systolic blood pressure (SBP) at 12 months in poorly controlled hypertensive patients. DESIGN: The ADAMPA study was a pragmatic, controlled, randomized, non-masked clinical trial with two parallel arms in Valencia, Spain. PARTICIPANTS: Hypertensive patients older than 40 years, with SBP over 145 mmHg and/or diastolic blood pressure (DBP) over 90 mmHg, were recruited from July 2017 to June 2018. INTERVENTION: Participants were randomized 1:1 to usual care versus an individualized, pre-arranged plan based on self-monitoring plus self-titration. MAIN MEASURE: The primary outcome was the adjusted mean difference (AMD) in SBP between groups at 12 months. KEY RESULTS: Primary outcome data were available for 312 patients (intervention n=156, control n=156) of the 366 who were initially recruited. The AMD in SBP at 12 months (main analysis) was -2.9 mmHg (95% CI, -5.9 to 0.1, p=0.061), while the AMD in DBP was -1.9 mmHg (95% CI, -3.7 to 0.0, p=0.052). The results of the subgroup analysis were consistent with these for the main outcome measures. More patients in the intervention group achieved good blood pressure control (<140/90 mmHg) at 12 months than in the control group (55.8% vs 42.3%, difference 13.5%, 95% CI, 2.5 to 24.5%, p=0.017). At 12 months, no differences were observed in behavior, quality of life, use of health services, or adverse events. CONCLUSION: Self-monitoring plus self-titration of antihypertensive medication based on an individualized pre-arranged plan used in primary care may be a promising strategy for reducing blood pressure at 12 months compared to usual care, without increasing healthcare utilization or adverse events. TRIAL REGISTRATION: EudraCT, number 2016-003986-25 (registered 17 March 2017) and clinicaltrials.gov , NCT03242785.

Real-world patterns of opioid therapy initiation in Spain, 2012-2018: A population-based, retrospective cohort study with 957,080 patients and 1,509,488 initiations.

Introduction: Europe has seen a steady increase in the use of prescription opioids, especially in non-cancer indications. Epidemiological data on the patterns of use of opioids is required to optimize prescription. We aim to describe the patterns of opioid therapy initiation for non-cancer pain and characteristics of patients treated in a region with five million inhabitants in the period 2012 to 2018. Methods: Population-based retrospective cohort study of all adult patients initiating opioid therapy for non-cancer pain in the region of Valencia. We described patient characteristics at baseline and the characteristics of baseline and subsequent treatment initiation. We used multinominal regression models to identify individual factors associated with initiation. Results: A total of 957,080 patients initiated 1,509,488 opioid treatments (957,080 baseline initiations, 552,408 subsequent initiations). For baseline initiations, 738,749 were with tramadol (77.19%), 157,098 with codeine (16.41%) 58,436 (6.11%) with long-acting opioids, 1,518 (0.16%) with short-acting opioids and 1,279 (0.13%) with ultrafast drugs. When compared to tramadol, patients initiating with short-acting, long-acting and ultrafast opioids were more likely to be older and had more comorbidities, whereas initiators with codeine were more prone to be healthier and younger. Treatments lasting less than 7 days accounted for 41.82% of initiations, and 11.89% lasted more than 30 days. 19.55% of initiators with ultrafast fentanyl received more than 120 daily Morphine Milligram Equivalents (MME), and 16.12% of patients initiating with long-acting opioids were prescribed more than 90 daily MME (p < 0.001). Musculoskeletal indications accounted for 65.05% of opioid use. Overlap with benzodiazepines was observed in 24.73% of initiations, overlap with gabapentinoids was present in 11.04% of initiations with long-acting opioids and 28.39% of initiators with short-acting opioids used antipsychotics concomitantly. In subsequent initiations, 55.48% of treatments included three or more prescriptions (vs. 17.60% in baseline initiations) and risk of overlap was also increased. Conclusion: Opioids are initiated for a vast array of non-oncological indications, and, despite clinical guidelines, short-acting opioids are used marginally, and a significant number of patients is exposed to potentially high-risk patterns of initiation, such as treatments lasting more than 14 days, treatments surpassing 50 daily MMEs, initiating with long-acting opioids, or hazardous overlapping with other therapies.

Side effects during the week after first dose vaccination with four Covid-19 vaccines. Results of the ProVaVac Survey Study with 13,837 people in Spain.

BACKGROUND: In 2021, four vaccines against Covid-19 (BNT162b2, mRNA-1273, ChAdOx1nCoV-19, and JNJ-78436735) were employed in the region of Valencia, Spain. We conducted a survey to identify real-world, self-reported frequency and severity of side effects during the week after vaccination. METHODS: Survey data was obtained from April 19, 2021, to October 6, 2021, at three different moments in time: day one, day three and day seven after vaccination. Answers were linked to individual-level, personal and clinical information. Respondents were stratified by the vaccine they received and reported effects were presented over time and stratified by severity. We compared our results per vaccine with the frequencies stated in each Summary of Product Characteristics (SmPC). We used binomial logistic models to identify associations between respondent characteristics and side effects. RESULTS: No symptoms were reported by 1,986 respondents (14.35 %), 6,254 informed exclusively mild symptoms (45.20 %), 3,444 up to moderate symptoms (24.89 %), and 2,153 people (15.56 %) notified also severe symptoms. Among the latter, the more frequent were extreme tiredness (7.0 %), and nausea or vomiting (7.1 %). The reported frequency of facial paralysis (0.4 %) was much higher than reflected in SmPCs. Female sex, younger age, previous positive Active Infection Diagnostic Test, chronicity, and vaccination with other than the BNT162b2 vaccine were associated to an increased risk of side effects (p < 0.001). CONCLUSIONS: Side effects after vaccination are common in the real-world. However, they are principally mild, and their frequency declines after a few days. Providing patients with dependable, beforehand information about side effects may improve outcomes and reinforce vaccination programs.

Assessing Concurrent Adherence to Combined Essential Medication and Clinical Outcomes in Patients With Acute Coronary Syndrome. A Population-Based, Real-World Study Using Group-Based Trajectory Models.

Aim: Adherence to multiple medications recommended for secondary prevention of cardiovascular conditions represents a challenge. We aimed to identify patterns of concurrent adherence to combined therapy and assess their impact on clinical outcomes in a cohort of patients with acute coronary syndrome (ACS). Methods: Population-based retrospective cohort of all patients discharged after hospitalization for ACS (2009-2011), prescribed ≥3 therapeutic groups within the first month. We assessed monthly concurrent adherence (≥24 days of medication out of 30) to ≥3 medications during the first year, and patterns were identified through group-based trajectory models. A composite clinical outcome during the second year was constructed. The association between adherence patterns and traditional refill adherence metrics [e.g., the proportion of days covered (PDC)], and outcomes were assessed through a multivariable Cox proportional hazards model. Results: Among 15,797 patients discharged alive, 12,057 (76.32%) initiated treatment with ≥3 therapeutic groups after discharge. We identified seven adherence trajectories to ≥3 medications: Adherent (52.94% of patients); Early Gap (6.64%); Middle Gap (5.67%); Late Decline (10.93%); Occasional Users (5.45%); Early Decline (8.79%); Non-Adherent (9.58%). Compared to the Adherent group, patients belonging to Early Gap (HR:1.30, 95%CI 1.07;1.60), Late decline (hazards ratio (HR): 1.31, 95% CI 1.1; 1.56), and Non-Adherent trajectories (HR: 1.36, 95% CI 1.14; 1.63) had a greater risk of adverse clinical outcomes, which was also different to the risk ascertained through concurrent PDC < 80 (HR: 1.13, 95% CI 1.01; 1.27). Conclusion: Overall, seven adherence trajectories to ≥3 drugs were identified, with three distinct adherence patterns being at higher risk of adverse outcomes. The identification of patterns of concurrent adherence, a more comprehensive approach than traditional measurements, may be useful to target interventions to improve adherence to multiple medications.

Predictive Performance of the FRAX Tool Calibrated for Spain vs. an Age and Sex Model: Prospective Cohort Study with 9082 Women and Men Followed for up to 8 Years.

In Spain, the Fracture Risk Assessment Tool (FRAX) was adapted using studies with a small number of patients, and there are only a few external validation studies that present limitations. In this prospective cohort study, we compared the performance of FRAX and a simple age and sex model. We used data from the ESOSVAL cohort, a cohort composed of a Mediterranean population of 11,035 women and men aged 50 years and over, followed for up to 8 years, to compare the discrimination, calibration, and reclassification of FRAX calibrated for Spain and a logistic model including only age and sex as variables. We found virtually identical AUC, 83.55% for FRAX (CI 95%: 80.46, 86.63) and 84.10% for the age and sex model (CI 95%: 80.91, 87.29), and there were similar observed-to-predicted ratios. In the reclassification analyses, patients with a hip fracture that were reclassified correctly as high risk by FRAX, compared to the age and sex model, were -2.86%, using either the 3% threshold or the observed incidence, 1.54% (95%CI: -8.44, 2.72 for the 3% threshold; 95%CI: -7.68, 1.97 for the incidence threshold). Remarkably simple and inexpensive tools that are easily transferable into electronic medical record environments may offer a comparable predictive ability to that of FRAX.

Impact of Three Safety Interventions Targeting Off-Label Use of Immediate-Release Fentanyl on Prescription Trends: Interrupted Time Series Analysis.

Background: The Spanish health authorities are concerned by the off-label use of immediate-release formulations of fentanyl (IRF) in noncancer pain and cancer pain in patients with no chronic pain therapy. Aim: To evaluate the impact of different interventions to improve appropriateness of IRF prescription on off-label prescription. Patients and methods: We used interrupted time series (ITS) to estimate immediate and trend changes of IRF prescription for noncancer pain (NCP) and breakthrough cancer pain (BCP) in patients with and without chronic cancer pain therapy associated with two medication reviews (I1 and I2) and the issue of a safety warning letter (I3) with data from a Spanish region with 5 million inhabitants, from 2015 to 2018. Results: The use of IRF for NCP in the region Valencia was reduced from about 1,800 prescriptions per week to around 1,400. The first medication review was followed by an immediate level change of -192.66 prescriptions per week (p < 0.001) and a downward trend change of -6.75 prescriptions/week (p < 0.001), resulting in a post-intervention trend of -1.99 (p < 0.001). I2 was associated with a trend change of -23.07 (p < 0.001) prescriptions/week. After I3, the trend changed markedly to 27.23 additional prescriptions/week, for a final post-intervention trend of 2.17 (p < 0.001). Controlled-ITS provided comparable results. For potentially inappropriate BCP use, the second medication review was followed by a downward, immediate level change of -10.10 prescriptions/week (p = 0.011) and a trend change of 2.31 additional prescriptions/week (p < 0.001) and the issue of the safety warning (I3) was followed by a downward trend change of -2.09 prescriptions/week (p = 0.007). Conclusion: Despite IRF prescription for NCP decreased, the interventions showed modest and temporary effect on off-label prescription. Our results call for a review of the design and implementation of safety interventions addressing inappropriate opioid use.

Incidence of Subsequent Hip Fracture and Mortality in Elderly Patients: A Multistate Population-Based Cohort Study in Eastern Spain.

Osteoporotic hip fractures in older people may confer an increased risk of subsequent hip fractures and death. The aim of this study was to estimate the cumulative incidence of both recurrent hip fracture and death in the Valencia region. We followed a cohort of 34,491 patients aged ≥65 years who were discharged alive from Valencia Health System hospitals after an osteoporotic hip fracture between 2008 and 2015, until death or end of study (December 31, 2016). Two Bayesian illness-death models were applied to estimate the cumulative incidences of recurrent hip fracture and death by sex, age, and year of discharge. We estimated 1-year cumulative incidences of recurrent hip fracture at 2.5% in women and 2.3% in men, and 8.3% and 6.6%, respectively, at 5 years. Cumulative incidences of total death were 18.3% in women and 28.6% in men at 1 year, and 51.2% and 69.8% at 5 years. One-year probabilities of death after recurrent hip fracture were estimated at 26.8% and 43.8%, respectively, and at 57.3% and 79.2% at 5 years. Our analysis showed an increasing trend in the 1-year cumulative incidence of recurrent hip fracture from 2008 to 2015, but a decreasing trend in 1-year mortality. Male sex and age at discharge were associated with increased risk of death. Women showed higher incidence of subsequent hip fracture than men although they were at the same risk of recurrent hip fracture. Probabilities of death after recurrent hip fracture were higher than those observed in the general population. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Association of Vitamin K and Non-Vitamin K Oral Anticoagulant Use and Cancer Incidence in Atrial Fibrillation Patients.

The association between the use of vitamin K antagonists (VKAs) and cancer risk reduction remains unclear. We aimed to assess the association between the use of VKAs or direct oral anticoagulants (DOACs) and the incidence of cancer in a large cohort of patients with atrial fibrillation (AF) by means of a population-based, propensity-weighted cohort study using population-wide databases including patients diagnosed with nonvalvular AF (NVAF) followed for up of 5 years (median 2.94 years). We created two cohorts based on the initiation therapy (VKA or DOAC). Initiation with VKA or DOAC was defined as filling a prescription with no previous exposure in the preceding 12 months. Cancer diagnoses of any type and for specific tumors (lung, colon, prostate, bladder, and breast). We included 39,989 patients, 31,200 (78.0%) in the VKA cohort. Incidence rate for any cancer was 12.45 per 1,000 person-year in the DOAC cohort vs. 14.55 in the VKA cohort (adjusted hazard ratio (HR): 1.16, 95% confidence interval (CI): 1.02-1.32). In secondary outcomes, no differences were found for specific types of cancer, such as lung (HR: 1.28, CI: 0.89-1.83), colon (HR: 0.84, CI: 0.62-1.13), prostate (HR: 1.40, CI: 0.94-2.10), bladder (HR: 1.07, CI: 0.76-1.52), and breast (HR: 1.05, CI: 0.66-1.69). Sensitivity analyses yielded similar results. Subgroup analyses also produced consistent findings, except for men, for whom VKA was associated with a lower risk of colon cancer (HR: 0.68, 95% CI: 0.48-0.96). Our results do not confirm a chemoprotective effect of VKA when compared with DOAC in a large, real-world cohort of patients with NVAF followed for up to 5 years.

Real-World Management and Clinical Outcomes of Stroke Survivors With Atrial Fibrillation: A Population-Based Cohort in Spain.

Objective: Despite the continuous update of clinical guidelines, little is known about the real-world management of patients with atrial fibrillation (AF) who survived a stroke. We aimed to assess patterns of therapeutic management of stroke survivors with AF and clinical outcomes using data from routine practice in a large population-based cohort. Methods: A population-based retrospective cohort study of all patients with AF who survived a stroke, from January 2010 to December 2017 in the Valencia region, Spain (n = 10,986), was carried out. Treatment strategies and mean time to treatment initiation are described. Temporal trends are shown by the management pattern during the study period. Factors associated with each pattern (including no treatment) vs. oral anticoagulant (OAC) treatment were identified using logistic multivariate regression models. Incidence rates of clinical outcomes (mortality, stroke/TIA, GI bleeding, and ACS) were also estimated by the management pattern. Results: Among stroke survivors with AF, 6% were non-treated, 23% were prescribed antiplatelets (APT), 54% were prescribed OAC, and 17% received OAC + APT at discharge. Time to treatment was 8.0 days (CI 7.6-8.4) for APT, 9.86 (CI 9.52-10.19) for OAC, and 16.47 (CI 15.86-17.09) for OAC + APT. Regarding temporal trends, management with OAC increased by 20%, with a decrease of 50% for APT during the study period. No treatment and OAC + APT remained relatively stable. The strongest predictor of no treatment and APT treatment was having the same management strategy pre-stroke. Those treated with APT had the highest rates of GI bleeding and recurrent stroke/TIA, and untreated patients showed the highest rates of mortality. Conclusion: In this large population-based cohort using real-world data, nearly 30% of AF patients who suffered a stroke were untreated or treated with APT, which overall is not recommended. Treatment was started within 2 weeks as recommended, except for OAC + APT, which was started later. The strong association of APT treatment or non-treatment with the same treatment strategy before stroke occurrence suggests a strong therapeutic inertia and opposes recommendations. Patients under these two strategies had the highest rates of adverse outcomes. An inadequate prescription poses a great risk on patients with AF and stroke; thus monitoring their management is necessary and should be setting-specific.

Clinical outcomes of nonvitamin K oral anticoagulants and acenocoumarol for stroke prevention in contemporary practice: A population-based propensity-weighted cohort study.

AIMS: Acenocoumarol is a vitamin-K antagonist (VKA) primarily used in certain countries (e.g. India, Netherlands, Spain). The half-life of acenocoumarol is similar to that of non-VKA oral anticoagulants (NOAC), unlike warfarin, and this could affect comparative effectiveness and safety (CES). However, data on CES for NOAC come almost exclusively from studies using warfarin as the comparator. We aimed to assess outcomes of NOAC and acenocoumarol in people with non-valvular atrial fibrillation (NVAF) in real-world clinical practice. METHODS: This is a population-based retrospective cohort study. All new users of oral anticoagulants from November 2011 to December 2015 with NVAF were included (n = 41,560). Data were obtained by linking several health electronic records of the Valencia region, Spain. Incidence rates were estimated. We used the inverse probability of treatment weighted Cox analysis to control for indication bias when assessing the risk of effectiveness and safety outcomes for each NOAC compared with acenocoumarol. Several sensitivity analyses were performed. RESULTS: We did not find differences in the risk of mortality, ischaemic stroke or any gastrointestinal bleeding. However, we did find a decreased risk of intracranial haemorrhage for dabigatran (HR: 0.34, 95% CI 0.20-0.56) and rivaroxaban (HR: 0.55, 95% CI 0.35-0.85) as compared to acenocoumarol. In subanalyses, apixaban showed a higher risk of ischaemic stroke in high-risk persons (≥75 years and CHA2DS2-VASC score ≥ 2). CONCLUSIONS: No differences in clinical outcomes were found between NOAC and acenocoumarol overall, although dabigatran and rivaroxaban showed a lower risk of intracranial haemorrhage. Findings on the potential inferiority of specific NOAC in high-risk subgroups should be studied further.

Primary care doctors' views on self-monitoring of blood pressure and self-titration among patients with uncontrolled hypertension in Spain. The ADAMPA trial focus group study.

BACKGROUND: Despite the increased use of blood pressure (BP) monitoring devices at home, the hypertension of more than 50% of European patients remains uncontrolled. Nevertheless, the self-management of BP, through the combination of home monitoring of BP with self-titration, could be anaccessible and effective tool for improving hypertension control in the primary care setting. The ADAMPA study is a trial with participants randomised to BP self-management (BPSM) with self-titration of antihypertensive medication or to usual care, in a population of patients with poorly controlled hypertension. AIM: To explore the views and attitudes of primary care doctors participating in the ADAMPA trial regarding BPSM with self-titration. DESIGN & SETTING: A focus group study took place with primary care doctors participating in the ADAMPA trial, which was carried out in one health district of the Valencia Health System in Spain. METHOD: Nine primary care doctors participating in the ADAMPA trial were included in the focus group. Three researchers (two using manual methods and one using NVivo software) independently conducted a content analysis, reading the transcripts, identifying, classifying, and coding the contents, and developing a conceptual scheme based on these topics. RESULTS: Participating doctors clearly support home BP monitoring (HBPM), the setting of individual BP targets, and incorporating patient readings into decision-making. They consider it an investment to educate patients for medication self-adjustment and estimate that an important proportion of their patients are potential candidates for hypertension self-management with medication self-titration. However, they show important divergences regarding the role of nursing in BP control. CONCLUSION: Primary care doctors participating in the ADAMPA trial feel comfortable with BPSM with self-titration, and would consider extending its use (or the use of some components, such as BP target setting) to other patients with hypertension outside the trial.

Trends and Geographical Variability in Osteoporosis Treatment After Hip Fracture: A Multilevel Analysis of 30,965 Patients in the Region of Valencia, Spain.

Despite improvements in the therapeutic arsenal and the recommendations of guidelines, low rates of prescribing osteoporosis medications are being reported worldwide for patients surviving a hip fracture, and important geographical variation remain. We aimed to describe trends in the proportion of patients that receive osteoporosis medication after hip fracture and to analyze the geographical variation in the prescription of drug therapy and its associated factors in the region of Valencia, Spain. We studied a population-based retrospective cohort of 30,965 patients aged 65 years and older, discharged from hospital after a hip fracture from January 2008 to December 2015, who were followed up for 3 months after discharge to identify the presence of any prescription of osteoporosis medication. We conducted a multilevel multiple logistic regression analysis with two levels (individuals and health departments [HD]) to determine which individual covariates were associated with receiving a prescription of osteoporosis medication in the 3 months after discharge, as well as the importance of the HD of hospitalization. The percentage of patients treated in the region decreased from a maximum of 28.9% in 2009 to 16.4% in 2015. By sex, the proportion of women treated reached a maximum of 33.4% in 2009 and declined to 19% in 2015, while the proportion of men reached a maximum of 14% in 2011 and reduced to 8.1% in 2015. By health department, there was a noticeable variability in the rate of patients treated, ranging from 40.9% to 11.1% in the whole period (intraclass correlation coefficient [ICC] = 7.54%; median odds ratio [MOR] = 1.64). Proportion of treated patients decreased in 20 of the 24 HDs. Variability could be also observed with regard to choice of medication by HD. This situation pressingly demands action (both at the organizational and professional levels) focused on populations at a higher risk (such as hip fracture patients) that particularly address underutilization and unwarranted variation.

The role of parental social class, education and unemployment on child cognitive development.

OBJECTIVE: Assessing the association between socioeconomic gradient and cognitive development among children of a Spanish birth cohort aged 5-6 years from a gender perspective. METHOD: Cognitive development was assessed on 525 children aged 5-6 years in the INMA-Valencia cohort, with the Global Cognitive Score (GCS) from McCarthy Scales of Children's Abilities. Information on social class, education level and employment was collected for both parents in addition to other sociodemographic factors, parental, family and child characteristics. The relationship between maternal and paternal socioeconomic gradient and cognitive development was assessed by linear regressions and comparing the variance explained by each indicator measured in the mother and father. RESULTS: Maternal socioeconomic gradient indicators explained more variance on GCS than paternal. Maternal education and paternal social class had an important individual effect that stayed after adjusting by other parental, child and family determinants. In the multivariable analysis, maternal education, age and intelligence, paternal social class and the child's age and sex were significantly associated with cognitive development. CONCLUSIONS: Diverse socioeconomic gradient factors have an important influence on cognitive development, maternal education being the strongest determinant. Policies should be implemented to mitigate the negative effects of this gradient on child development.