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.

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.

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.

Group-based Trajectory Models to Assess Quality of INR Control and Its Association With Clinical Outcomes.

BACKGROUND: The Time in Therapeutic Range (TTR) is the gold-standard measure used to assess the quality of oral anticoagulation with vitamin K antagonists. However, TTR is a static measure, and International Normalized Ratio (INR) control is a dynamic process. Group-based Trajectory Models (GBTM) can address this dynamic nature by classifying patients into different trajectories of INR control over time. OBJECTIVES: The objective of this study was to assess the quality of INR control in a population-based cohort of new users of vitamin K antagonist with a diagnosis of atrial fibrillation using GBTM. METHODS: We classified patients into different trajectories according to their propensity for being adequately anticoagulated over their first year of treatment using GBTM, and we evaluated the association between trajectories and relevant clinical outcomes over the following year. RESULTS: We included 8024 patients in the cohort who fulfilled the inclusion criteria; the mean number of INR determinations over the first year of treatment was 13.9. We identified 4 differential trajectories of INR control: Optimal (9.7% of patients, TTR: 83.8%), Improving (27.4% of patients, TTR: 61.2%), Worsening (28%; TTR: 69.1%), and Poor control (34.9%; TTR: 41.5%). In adjusted analysis, Poor and Worsening control patients had a higher risk of death than Optimal control patients (hazard ratio: 1.79; IC 95%, 1.36-2.36 and hazard ratio: 1.36; IC 95%, 1.02-1.81, respectively). Differences in other outcomes did not achieve statistical significance, except for a reduced risk of transient ischemic attack in the Improving Control group. CONCLUSIONS: GBTM may contribute to a better understanding and assessment of the quality of oral anticoagulation and may be used in addition to traditional, well-established measures such as TTR.

Poor mothers, unhealthy children: the transmission of health inequalities in the INMA study, Spain.

BACKGROUND: The health of pregnant women and their fetuses are especially sensitive to socioeconomic conditions. This study analyzes the impact of maternal socioeconomic status (SES), evaluated by occupation and maternal education level, in preterm births (PTBs) and in small for gestational age (SGA) fetuses, considering the effect of the potential mediating factors on the SES and birth outcomes. METHODS: A total of 2497 mother/newborn dyads from the INMA-Spain project were studied. We examined maternal occupation and education in relation to PTB and SGA along with covariate data, using logistic regression analysis. Adjusted models for each of the outcome variables in relation to SES indicators were estimated, considering potential mediating factors. RESULTS: About 4.7% of babies were PTB and 9.7% SGA. Full adjusted logistic regression models showed similar odds ratio (OR) for SGA in both SES indicators. Manual working women or without university studies had higher risk of SGA than their counterpart groups (OR = 1.39% CI = 1.03-1.88 and OR = 1.39% CI = 1.00-2.00, respectively). Likewise, mothers with a manual occupation were at more risk of PTB than those with a non-manual occupation (OR = 1.74 95% CI = 1.13-2.74), but there was no association between education and PTB. Smoking, pre-pregnancy BMI and underweight gain during pregnancy were significantly associated to SGA births. The mother's age, presence of complications and overweight gain during pregnancy were related to PTB. CONCLUSION: The mother's socioeconomic disadvantage was consistently associated with birth outcomes giving rise to intergenerational transmission of health inequalities. Reducing inequalities requires eliminating the upstream causes of poverty itself.

Rationale and design of a pragmatic clinical trial to assess the impact of self-monitoring blood pressure at home and self-titration of antihypertensive medication in poorly controlled hypertension: the ADAMPA study protocol.

BACKGROUND: Lack of control of hypertension is one of the most prevalent problems encountered by general practitioners (GPs). Self-measured blood pressure monitoring at home (SMBP) and self-titration of medication could be a good strategy to improve hypertension management, however, evidence is limited and not conclusive. We aimed to assess the effectiveness, in the primary care setting, of an intervention that includes educational components, SMBP and self-titration of antihypertensive medication to decrease systolic blood pressure compared to usual care, in a population with poorly controlled hypertension, during a 12-month period. METHODS: Pragmatic, controlled, randomized, unblinded clinical trial with two parallel groups assigned in a ratio of 1:1 to self-management (which includes educational components, SBMP and self-titration of antihypertensive medication based on a patient's GP's pre-established adjustment plan) or to usual care (with educational components too). DISCUSSION: If the data from this trial show positive results, the study may contribute to a change of strategy in the treatment of hypertension, focusing on the patient as the main actor to achieve blood pressure control. Furthermore, this approach might contribute to the financial sustainability of the National Health Service. TRIAL REGISTRATION: This trial has been registered in the database with reference number EudraCT: 2016-003986-25. Registered 05 May 2017, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2016-003986-25.

Association of light-to-moderate alcohol drinking in pregnancy with preterm birth and birth weight: elucidating bias by pooling data from nine European cohorts.

Women who drink light-to-moderately during pregnancy have been observed to have lower risk of unfavourable pregnancy outcomes than abstainers. This has been suggested to be a result of bias. In a pooled sample, including 193 747 live-born singletons from nine European cohorts, we examined the associations between light-to-moderate drinking and preterm birth, birth weight, and small-for-gestational age in term born children (term SGA). To address potential sources of bias, we compared the associations from the total sample with a sub-sample restricted to first-time pregnant women who conceived within six months of trying, and examined whether the associations varied across calendar time. In the total sample, drinking up to around six drinks per week as compared to abstaining was associated with lower risk of preterm birth, whereas no significant associations were found for birth weight or term SGA. Drinking six or more drinks per week was associated with lower birth weight and higher risk of term SGA, but no increased risk of preterm birth. The analyses restricted to women without reproductive experience revealed similar results. Before 2000 approximately half of pregnant women drank alcohol. This decreased to 39% in 2000-2004, and 14% in 2005-2011. Before 2000, every additional drink was associated with reduced mean birth weight, whereas in 2005-2011, the mean birth weight increased with increasing intake. The period-specific associations between low-to-moderate drinking and birth weight, which also were observed for term SGA, are indicative of bias. It is impossible to distinguish if the bias is attributable to unmeasured confounding, which change over time or cohort heterogeneity.

Trends and area variations in Potentially Preventable Admissions for COPD in Spain (2002-2013): a significant decline and convergence between areas.

BACKGROUND: Potentially Preventable Hospitalizations (PPH) are hospital admissions for conditions which are preventable with timely and appropriate outpatient care being Chronic Obstructive Pulmonary Disease (COPD) admissions one of the most relevant PPH. We estimate the population age-sex standardized relative risk of admission for COPD-PPH by year and area of residence in the Spanish National Health System (sNHS) during the period 2002-2013. METHODS: The study was conducted in the 203 Hospital Service Areas of the sNHS, using the 2002 to 2013 hospital admissions for a COPD-PPH condition of patients aged 20 and over. We use conventional small area variation statistics and a Bayesian hierarchical approach to model the different risk structures of dependence in both space and time. RESULTS: COPD-PPH admissions declined from 24.5 to 15.5 per 10,000 persons-year (Men: from 40.6 to 25.1; Women: from 9.1 to 6.4). The relative risk declined from 1.19 (19 % above 2002-2013 average) in 2002 to 0.77 (30 % below average) in 2013. Both the starting point and the slope were different for the different regions. Variation among admission rates between extreme areas dropped from 6.7 times higher in 2002 to 4.6 times higher in 2013. CONCLUSIONS: COPD-PPH conditions in Spain have undergone a strong decline and a reduction in geographical variation in the last 12 years, suggesting a general improvement in health policies and health care over time. Variability among areas still remains, with a substantial room for improvement.

Vitamin D in Pregnancy and Attention Deficit Hyperactivity Disorder-like Symptoms in Childhood.

BACKGROUND: Vitamin D status during prenatal brain development may influence risk of attention deficit and hyperactivity disorder (ADHD) symptoms in childhood. However, there are no prospective studies addressing this hypothesis. We aimed to examine whether maternal vitamin D status in pregnancy is associated with risk of ADHD-like symptoms in offspring. METHODS: We conducted a prospective study analyzing data from 1,650 mother-child pairs from five birth cohorts embedded in the INMA Project (Spain, 1997-2008). Maternal vitamin D status in pregnancy was estimated by measuring plasma concentration of 25-hydroxyvitamin D3 [25(OH)D3] at 13 weeks of gestation. Children were assessed by teachers for ADHD-like symptoms at ages 4-5 years using the Diagnostic and Statistical Manual of Mental Disorders ADHD form list. RESULTS: After adjustment, the number of total ADHD-like symptoms in children decreased by 11% per 10 ng/ml increment of maternal 25(OH)D3 concentration (incidence rate ratio [IRR] = 0.89; 95% confidence interval [CI] = 0.80, 0.98). Similarly, the number of symptoms in the ADHD subscales decreased in relation to higher maternal 25(OH)D3 concentration (IRR per 10 ng/ml increment = 0.89; 95% CI = 0.79, 0.99 for the inattention scale; and IRR = 0.88; 95% CI = 0.78, 0.99 for the hyperactivity-impulsivity scale). Using diagnostic criteria, we found an association of increasing maternal 25(OH)D3 with a lower risk of ADHD DSM-IV (relative risk ratio per 10 ng/ml increment = 0.87; 95% CI = 0.72, 1.06) and ICD-10 hyperkinetic disorder (relative risk ratio = 0.72; 95% CI = 0.49, 1.04) in children. CONCLUSION: Higher maternal circulating levels of 25(OH)D3 in pregnancy are associated with lower risk of developing ADHD-like symptoms in childhood.

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.

Long-term diet quality is associated with lower obesity risk in young African American women with normal BMI at baseline.

The prevalence of obesity [body mass index (BMI) ≥30 kg/m2] is high among African American women, with most weight gain occurring before middle age. We assessed diet quality, as measured by the Alternate Healthy Eating Index-2010 (AHEI-2010) and the Dietary Approaches to Stop Hypertension (DASH) diet score in relation to incident obesity in the Black Women's Health Study. Prospective data were collected via biennial questionnaires from 1995 to 2011. AHEI-2010 and DASH scores were calculated from food-frequency questionnaire data collected in 1995 and 2001. We restricted the analysis to 19,885 nonobese women aged 21-39 y at baseline. Multivariable Cox regression was used to estimate HRs and 95% CIs. Among women with consistent diet scores in 1995 and 2001, higher diet quality scores were inversely associated with obesity incidence: the multivariable HRs comparing highest with lowest quintiles of the AHEI-2010 and DASH scores were 0.76 (95% CI: 0.58, 0.98) and 0.68 (95% CI: 0.53, 0.88), respectively, among women with a BMI in the normal range (18.5-24.9 kg/m2) at baseline. There were no significant associations among women who were overweight at baseline. The findings suggest that a high-quality diet that is sustained over time is associated with reduced obesity risk among young African American women with a normal BMI at baseline.

Dietary intake in pregnant women in a Spanish Mediterranean area: as good as it is supposed to be?

OBJECTIVE: To assess food and nutrient intakes and compliance with nutritional recommendations in pregnant women according to selected sociodemographic characteristics. DESIGN: Cross-sectional study based on data from the INMA-Valencia cohort (Spain), which recruited pregnant women between 2004 and 2005. Information on maternal sociodemographics and anthropometry was collected. Dietary intake was assessed through an FFQ. Intakes of foods were compared with Spanish food-based dietary guidelines. Intake inadequacy for nutrients was assessed using the Dietary Reference Intakes of the US Institute of Medicine. SETTING: Valencia, Spain. SUBJECTS: We studied 822 pregnant women who had information on dietary intake during their first trimester of pregnancy. RESULTS: More than 50% of pregnant women did not meet the guidelines for cereals and legumes; reported intakes of carbohydrates, n-3 and n-6 fatty acids were below recommendations and exceeded the total fat intake according to dietary references. Dietary inadequacy for folate, Fe and vitamin E ranged from 99% to 68%. Vegetable intake was related to age only. Younger and less educated women showed lower intakes of protein and n-3 fatty acids and higher intakes of trans-fatty acids as well as greater inadequacy for micronutrients. Spanish women reported lower intakes of fruit and carbohydrates and higher intakes of protein, total fat, SFA, MUFA and n-3 fatty acids compared with their foreign-born counterparts. CONCLUSIONS: Women in the studied area have inadequate intakes of several nutrients relevant during pregnancy. Age, education and country of origin are factors significantly related to dietary intake and adequacy.

Socio-economic inequalities in health, habits and self-care during pregnancy in Spain.

Socioeconomic disadvantage can be harmful for mother's health and can influence child's health long term. The aim of this study is to analyse social inequalities between pregnant women from four INMA (INfancia y Medio Ambiente) cohorts. The analysis included 2,607 pregnant women recruited between 2004 and 2008 from four INMA cohorts. Data on maternal characteristics were collected through two questionnaires completed in the first and third trimester of pregnancy. The relationship between socioeconomic status (SES) and maternal health, dietary intake, lifestyle habits and self-care related variables was modelled using logistic regression analysis. 33.5 % of women had a university level of education and 47 % had high occupational class. Women with higher SES reported healthier habits, fewer complications during pregnancy, better weight gain control and attended more prenatal appointments than women with lower SES. The risk of sedentary behaviour and passive smoking was higher among women with a lower level of education (OR = 1.7, 95 % CI 1.3-2.2 and OR = 1.6, 95 % CI 1.2-2.3, respectively) and with less skilled occupations (OR = 1.7, 95 % CI 1.4-2.0 and OR = 1.2, 95 % CI 1.0-1.5, respectively). Although both SES indicators-occupation and education-act as social determinants of diet, occupation was a more powerful determinant than education. For other lifestyle and self-caring variables, education was a more powerful predictor than occupation. Social inequalities were observed in health, habits and self-care during pregnancy. Proper care during pregnancy requires the control of common clinical variables and the knowledge of socioeconomic conditions of the pregnant women.

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.

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.

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.

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.

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.