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Purpose: We aimed to estimate the absolute (incidence) and relative (hazard ratio; HR) risk of agranulocytosis associated with metamizole in comparison with non-steroidal antiinflammatory drugs (NSAIDs). Methods: A cohort study of new users of metamizole versus NSAIDs was performed with BIFAP (Pharmacoepidemiologic Research Database in Public Health Systems; Spain). Patients aged ≥ 2 years in 2005–2022 were followed up from the day after their first metamizole or NSAID dispensation till the end of the treatment period to identify patients hospitalized due to idiosyncratic agranulocytosis. Incidence rate (IR) and adjusted HR of agranulocytosis with metamizole versus NSAID were estimated assuming the onset date of agranulocytosis was the date of hospitalization sensitivity analysis or 7 days before (main analysis). In secondary analyses, we used (1) opioids-paracetamol as negative control and (2) any hospitalized neutropenia as outcome (assuming the onset was 7 days before). Results: The cohorts included 444,972 new users of metamizole, 3,814,367 NSAID, and 3,129,221 opioids-paracetamol on continuous treatment during a median of 37–40 days. Overall, 26 hospitalized agranulocytosis occurred, 5 in the first week (and so removed in main analysis) and 21 thereafter. IR of agranulocytosis was 14.20 (N = 5 cases) and 8.52 (N = 3), 1.95 (N = 6) and 1.62 (N = 5), and 4.29 (N = 15) and 3.72 (N = 13)/107 person-weeks of continuous treatment using the date of hospitalization or 7 days before, respectively. Two, 0 and 2 of cases identified in both analyses had neoplasia in every cohort, respectively. HR of agranulocytosis associated with metamizole was 7.20 [95% CI: 1.92–26.99] and 4.40 [0.90–21.57] versus NSAID, and 3.31 [1.17–9.34] and 2.45 [0.68–8.83] versus opioid-paracetamol, respectively. HR of neutropenia with metamizole was 2.98 [1.57–5.65] versus NSAID. Conclusions: Agranulocytosis was very rare but more common (above 4 times more) with metamizole than other analgesics. The impact of the drug-induced agranulocytosis was less precise with metamizole than the comparators due to its lower use, which precluded to find statistical differences in main analysis. The increased risk of hospitalized neutropenias with metamizole supports the link with its severity although triggers unavailable during the follow-up (ex. cytotoxic medication) can not be discarded. [ABSTRACT FROM AUTHOR]

Introduction: A link between the human papillomavirus vaccination (HPVv) and inflammatory bowel disease (IBD) has been suggested. Objective: We aimed to estimate the risk of IBD following HPVv compared with periods not exposed to the vaccines. Methods: Primary healthcare records (Spanish Primary Care Database For Pharmacoepidemiological Research [BIFAP]) were used in a cohort study of girls in Spain aged 9–18 years between 2007 and 2016 free of IBD or HPVv at study entrance. During the follow-up to IBD diagnosis, time-varying HPVv exposure and confounders were assessed in Cox models to estimate the hazard ratio (HRs) of IBD in the 2 years after HPVv (exposed period) and thereafter (post-exposed) compared with the no exposure periods. In a post hoc analysis, we moved the IBD date back 30 days as a theoretical delay in diagnosis confirmation. Results: The cohort comprised 388,669 girls; 154,174 of these received the HPVv, and 88 IBD cases occurred (55 non-exposed, 22 exposed [after first N = 6, second N = 2, or third N = 14 dose] and 11 in post-exposed periods). The adjusted HR was 1.66 (95% confidence interval [CI] 0.68–4.05) for exposed and 1.10 (95% CI 0.37–3.24) for post-exposed periods. The HR for the first dose was 3.94 (95% CI 1.19–13.02). No association was found for the second or third doses. Post hoc, the HR was 1.83 (95% CI 0.72–4.69) for exposed periods (N = 18), and 1.84 (95% CI 0.35–9.83; N = 2), 1.50 (95% CI 0.40–5.63; N = 4) and 1.98 (95% CI 0.71–5.49; N = 12) after the first, second and third doses, respectively. Conclusions: This study did not show an increased risk of IBD following 2 years of HPVv exposure. However, an increased risk of IBD diagnosis was observed following the first vaccination dose (1–34 days), which is likely attributable to the clinical recommendation to vaccinate upon onset of IBD symptoms. [ABSTRACT FROM AUTHOR]

Introduction: The public–private ADVANCE collaboration developed and tested a system to generate evidence on vaccine benefits and risks using European electronic healthcare databases. In the safety of vaccines, background incidence rates are key to allow proper monitoring and assessment. The goals of this study were to compute age-, sex-, and calendar-year stratified incidence rates of nine autoimmune diseases in seven European healthcare databases from four countries and to assess validity by comparing with published data. Methods: Event rates were calculated for the following outcomes: acute disseminated encephalomyelitis, Bell's palsy, Guillain–Barré syndrome, immune thrombocytopenia purpura, Kawasaki disease, optic neuritis, narcolepsy, systemic lupus erythematosus, and transverse myelitis. Cases were identified by diagnosis codes. Participating organizations/databases originated from Denmark, Italy, Spain, and the UK. The source population comprised all persons registered, with at least 1 year of data prior to the study start, or follow-up from birth. Stratified incidence rates were computed per database over the period 2003 to 2014. Results: Between 2003 and 2014, 148,947 incident cases of nine autoimmune diseases were identified. Crude incidence rates were highest for Bell's palsy [23.8/100,000 person-years (PYs), 95% confidence interval (CI) 23.6–24.1] and lowest for Kawasaki disease (0.7/100,000 PYs, 95% CI 0.6–0.7). Specific patterns were observed by sex, age, calendar time, and data sources. Rates were comparable with published estimates. Conclusion: A range of autoimmune events could be identified in the ADVANCE system. Estimation of rates indicated consistency across selected European healthcare databases, as well as consistency with US published data. [ABSTRACT FROM AUTHOR]

Background: In Spain, girls are vaccinated against human papillomavirus (HPV) in the primary care setting, according to a national vaccination programme. Vaccination is voluntary and is covered by the public health system. Objectives: The aim of the study was to estimate the incidence and patterns of HPV vaccination amongst girls in primary care in Spain. Methods: A cohort study was performed using the information recorded in the Spanish Primary Care Database for Pharmacoepidemiological Research (BIFAP) from 7.9 million patients from seven Spanish regions, between 2001 and 2016 (56.6% of the regional population). Data available in BIFAP include patient age, sex, life-style factors, clinical events, specialist referrals, prescriptions, and vaccinations as recorded by the primary care physician (PCP) or administering nurse. The study cohort comprised all girls aged 9–18 years registered in BIFAP between 1st January of 2007 and 31st December of 2016 who had at least 1 year of clinical record information with their PCP (inclusion criteria). The date the inclusion criteria were met was designated as the start date to the study cohort contribution. In order to estimate the incidence of HPV vaccination (initiation of vaccination schedule), girls with an HPV vaccination recorded before the start date or without vaccination date were excluded. Girls forming the study cohort were followed from start date until there was a recorded HPV vaccination, they reached 19 years of age or died, end of available information, or 31st December 2016. The person-time of all patients forming the study cohort was reckoned in the incidence estimations. The follow-up was replicated yearly from 2007 to 2016. The cumulative incidence (CuIn) of vaccination by birth cohort, year and region, was estimated using life tables (proportion of vaccination by intervals in which the denominator is the initial population corrected for losses). Results: Of 388,690 girls forming the study population, 154,211 initiated the vaccination during 2007–2016. Ages ranged from 12 to 14 years at first dose in 84.5% of vaccinated girls, 42.79% received a quadrivalent vaccine, 21.86% a bivalent vaccine, and 35.35% an unknown type. Of the vaccinated population, 48.0% were completely vaccinated with a three-dose schedule and 28.9% with a two-dose schedule, 20.2% received one dose and 3.0% two doses in a three-dose schedule, at a maximum of 10 years of follow-up. The CuIn was highest among girls aged either 13 or 14 years over all regions (reaching 92.8% and 89.7%, respectively), and aged 12 in some regions/years (up to 89.8%). Girls aged 15 years were also vaccinated (although showing lower yearly incidence, i.e. < 69.1%) in two regions. The coverage was broadened to younger girls (11 years) during the last years of the study period in some regions. Conclusions: According to BIFAP primary care data, a high incidence of vaccination among girls aged 13–14 years was observed. Vaccination among younger and older girls were less common, although they reached high incidence in some regions and/or years. Most vaccination patterns adjusted to a complete vaccination regimen, as recommended posology. [ABSTRACT FROM AUTHOR]

Background: In Spain, girls and women are vaccinated against human papillomavirus (HPV) in the primary care setting, according to a national vaccination program. Vaccination is voluntary and the cost is covered by the public health system. Objectives: The aim of the study was to estimate the incidence and patterns of HPV vaccination amongst girls in Spain. Methods: A cohort study was performed using the information recorded in the Spanish Primary Care Database for Pharmacoepidemiological Research (BIFAP) from 7.4 million patients from eight Spanish regions, between 2001 and 2013 (56% of the regional population). Data available in BIFAP include patient age, sex, lifestyle factors, clinical events, specialist referrals, prescriptions, and vaccinations as recorded by the primary care physician (PCP) or administering nurse. The study cohort comprised all girls aged 11–18 years registered in BIFAP between 1 January 2007 and 31 December 2013 who had at least 1 year of clinical record information with their PCP (inclusion criteria). The date the inclusion criteria were met was designated as the start date of the study cohort contribution. In order to estimate the incidence of HPV vaccination, girls forming the study cohort were followed from start date until there was a recorded HPV vaccination, they reached 19 years of age or died, the end of available information, or 31 December 2013. The person-time of all patients forming the study cohort was taken into account in the incidence estimations. The cumulative incidence (CuIn) of vaccination by birth cohort, year and region was estimated using life-tables (proportion of vaccination by intervals in which the denominator is the initial population corrected for losses). Results: Out of 273,098 girls forming the study population, 81,461 were vaccinated during 2007–2013. Age ranged from 12 to 14 years at first dose in 86.0% of vaccinated girls; 54.1% received a quadrivalent vaccine, 21.9% a bivalent vaccine, and 24.0% an unknown type. Out of the vaccinated population, 87.9% received three doses, 8.2% two and 3.9% one dose, at a maximum of 7 years of follow-up. By calendar year and region, the CuIn reached 70.0–95.8% for birth cohorts between 1993 and 1999, 28.6–99.0% for births cohorts between 1990 and 1992, and exceptionally, 70.6–99.8% for births cohorts between 2000 and 2002 in three regions. Conclusions: According to BIFAP primary care data, a high incidence of vaccination among girls aged 13–15 years was observed. Vaccination among younger and older girls was less common although they reached high incidence in those regions that included girls aged 11–18 years in mass programs. Most vaccination patterns adjusted to a three-dose regimen, as recommended. [ABSTRACT FROM AUTHOR]

Purpose: To estimate the specific incidences of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) among new users of drugs frequently reported to be associated with this serious event.Methods: We performed a case-population approach, which combined data from a registry of SJS/TEN cases from the Madrid region (numerator) during the study period 2005-2015 and a primary healthcare database from the same catchment population. The proportion of new users of drugs estimated in the primary healthcare database was stratified by calendar year, sex and age (5-year bands), and then applied to the same strata of Madrid's population census to compute the number of new users (denominator). Incidences were re-estimated using only cases in which the concerned drug had a probable or very probable causal relationship.Results: A total of 44 SJS/TEN cases aged > 14 years were registered during the study period. The highest SJS/TEN incidence was found for phenytoin with 68.9 per 100,000 new users (95% CI 27.7-141.9), followed by dexamethasone (5.48; 1.49-14.03), allopurinol (3.29; 1.07-7.67) and cotrimoxazole (3.19; 0.87-8.16). Considering only probable and very probable cases, the incidences hardly changed, except for dexamethasone, which was left without cases. Pantoprazole, levofloxacin and lorazepam showed incidences between 1 per 100,000 and 1 per 1,000,000 new users. Ibuprofen, amoxicillin-clavulanic acid, metamizole, amoxicillin, paracetamol and omeprazole showed incidences around 1 per one million new users.Conclusions: Phenytoin was the drug with the highest incidence of SJS/TEN, followed by allopurinol and cotrimoxazole. For the rest of the drugs, the estimated incidences were below 1 in 100,000 new users. [ABSTRACT FROM AUTHOR]

Summary: Among 95,057 patients ≥50 years with new anti-osteoporosis medications (AOM) (2001-2013) in primary care, 1-year cessation was 51% (28%-68%), higher in men, smokers, patients with missing lifestyle data, and out normal BMI, and lower in those aged 60-79, with recent fractures or other anti-osteoporotics, suggesting non-severe osteoporosis and less risk awareness. Purpose: Low compliance to anti-osteoporosis medications (AOM) has been previously reported. We aimed to estimate 1-year cessation rates of different AOMs as used in Spanish healthcare settings, and to identify associated risk factors. Methods: A cohort study was performed using primary care records data (BIFAP). Patients entered the cohort when aged 50 years in 2001-2013, with ≥1 year of data available, and identified as incident users of AOM (1-year washout). Participants were divided into six cohorts: alendronate, other oral bisphosphonates, selective oestrogen receptor modulators, strontium ranelate, teriparatide, and denosumab. Patients were followed from therapy initiation to the earliest of cessation (90-day refill gap), switching (to alternative AOM), loss to follow-up, death, or end of 2013. One-year therapy cessation was estimated using life tables. Hazard ratios (of cessation) according to age, sex, lifestyle factors, morbidity, and co-medication were estimated after stepwise backwards selection. Results: A total of 95,057 AOM users were identified (91% women; mean age 68). One-year cessation was 51% overall, highest for strontium ranelate (68%), and lowest for denosumab (28%). Cessation probability was higher in men (14% to 2.1-fold), smokers (>6%), and patients with missing BMI (19-28%) or smoking (6-20%) data, and overweight/obese/underweight (7% to 2.6-fold increase compared to normal weight). Patients aged 60-79 years, with a recent fracture or other drugs used for osteoporosis, had better persistence. Conclusions: Over half of the patients initiating AOM stopped therapy within the first year after initiation. The described risk factors for cessation could be proxies for non-severe osteoporosis, and/or disease/risk awareness, which could inform the targeting of high-risk patients for monitoring and/or interventions aimed at improving persistence. [ABSTRACT FROM AUTHOR]

Purpose: We aim to estimate the incidence of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) among tetrazepam users and compare it with benzodiazepine users in a Spanish primary care database (BIFAP). The incidence in the general population (GenPop) and among phenytoin new users (as a positive control) was also estimated. Methods: We identified a cohort of GenPop free of SJS/TEN ( N = 3,155,364). Cohort entry was the date after 1 year of register with the physician during 2001-2011. No age restrictions were applied. Patients were followed from entry up to the first of the following: a record of SJS/TEN (potential cases), death, end of information, or December 2011. History of potential cases were manually reviewed blinded to exposure and considered 'probable' when diagnosed in referral reports. Three cohorts of patients newly prescribed with benzodiazepines ( N = 531,813), tetrazepam ( N = 343,568), or phenytoin ( N = 4993) were extracted from the GenPop cohort. Incidence rate (cases per million person-years (py)) for the GenPop and cumulative incidence (per million new users) during the first 9 weeks after each drug prescription were computed. Results: In the GenPop, 48 probable cases (38 SJS and 10 TEN) were identified (3.21/million py; 3.37 in men and 2.94 in women). In the benzodiazepines cohort, 2 probable TEN cases was identified (3.76/mill.). In the tetrazepam cohort, 1 probable SJS/TEN case was identified (2.91/mill.). In the phenytoin cohort, 4 probable cases (2 SJS and 2 TEN) were identified (801.12/mill.). Conclusions: The incidence of SJS/TEN in tetrazepam users was very rare and similar to benzodiazepines users. The incidence in the GenPop and among users of phenytoin agreed with the literature. [ABSTRACT FROM AUTHOR]

In this retrospective database study, carried out using The Health Improvement Network, a UK primary care database, we followed up patients who were prescribed low-dose acetylsalicylic acid (ASA) (75-300 mg/day) for the secondary prevention of cardiovascular disease in 2000-2007, and who discontinued therapy for a period of at least 90 days during that time ( n = 11,565). We assessed the incidence of, and factors associated with, ASA represcription. Patients were followed up from the first day after their initial 90-day period of discontinuation (start date) until ASA represcription, death, or the end of the study period (31 December 2010). Hazard ratios for factors associated with represcription were calculated using Cox regression models. The cumulative incidence of ASA represcription was 85.2 % over the entire follow-up period, and 63.5 % of all represcriptions were received in the first 6 months after patients' start dates. Factors significantly associated with a reduced likelihood of ASA represcription included being aged 75-84 years, cardiovascular and gastrointestinal comorbidities (in particular, atrial fibrillation and high overall gastrointestinal risk), adverse drug reactions experienced during therapy, and use of gastroprotective or cardiovascular medications (most notably warfarin). Factors significantly associated with an increased likelihood of ASA represcription included obesity, diabetes mellitus, stable angina, depression, and use of non-steroidal anti-inflammatory drugs. In conclusion, approximately 85 % of patients who discontinued low-dose ASA therapy were subsequently represcribed ASA during the study period. Comorbidities and comedication use affected represcription rates. [ABSTRACT FROM AUTHOR]

Background: Few studies have evaluated the prevention of upper gastrointestinal complications (UGIC; bleeding or perforation) in patients with uncomplicated peptic ulcer (PU). We assessed the effect of proton pump inhibitors (PPI) in a non-randomized setting. To maximize exchangeability of exposed and unexposed groups we restricted the study to patients with a new diagnosis of PU, i.e., a clear indication. To minimize selection bias we mimicked an intention to treat approach by assessing the effect of PPI prescription after PU diagnosis. Methods: Within a population of subjects aged 40-84 years from The Health Improvement Network database, 1997-2006, we identified 3,850 patients with incident PU. Among them, we confirmed 74 first UGIC episodes during a mean follow-up of 4 years. Exposure was prescription coverage during the month following PU diagnosis. We performed a nested case-control analysis and compared UGIC cases with 400 controls matched for age, sex, year and duration of follow-up. Relative risks (RR) and 95 % confidence intervals (CI) were estimated. Results: The overall incidence of UGIC was 4.6 cases/1,000 person-years; it was highest during the months after PU diagnosis, increased with age, and it was higher in men and subjects with Helicobacter pylori infection, anemia, and alcohol use at PU diagnosis. The RR for UGIC associated with PPI prescriptions during the month after PU diagnosis was 0.56 (95 % CI 0.31-1.0). The RR for NSAIDs with and without a PPI was 1.72 (0.68-4.45) and 3.27 (0.85-12.67), respectively. Conclusions: Findings suggest that prescription of PPIs after a PU diagnosis is associated with a reduced risk of UGIC. [ABSTRACT FROM AUTHOR]

Background: Androgen deprivation therapy (ADT) is used to delay tumour development and improve survival in patients with prostate cancer. However, several randomized controlled trials and observational studies have suggested that ADT may increase the risk of cardiovascular events.Objective: The aim of the study was to evaluate the risk of coronary heart disease (CHD) and heart failure (HF) in patients with prostate cancer receiving ADT in UK primary care, and to evaluate the risks associated with individual ADT and combination ADT.Methods: The UK General Practice Research Database was used to identify a cohort of patients with a first prostate cancer diagnosis during 1999-2005. These patients were followed up to assess the occurrence of acute myocardial infarction (AMI), death from CHD, incident HF and hospitalization due to acute decompensated HF. Nested case-control analyses were performed to assess the risk of these outcomes associated with anti-androgen therapy, as well as different types of ADT and combinations of ADT.Results: Current anti-androgen use was associated with a significant increase in the risk of hospitalization due to HF (odds ratio [OR] 2.15; 95% CI 1.08, 4.29), but not of incident HF, CHD or AMI. When assessed individually, there was no significant association of bicalutamide or cyproterone use with the risk of AMI or CHD. Current use of bicalutamide 50 mg/day was associated with a significant increase in the risk of HF (OR 3.28; 95% CI 1.31, 8.18); however, this increased risk of HF was only found in patients taking bicalutamide 50 mg/day in combination with luteinizing hormone-releasing hormone (LHRH) receptor agonists. There were no cases of hospitalized HF in patients taking bicalutamide 50 mg/day as monotherapy and there was no significant association between current use of bicalutamide 150 mg/day and the risk of hospitalized HF. Combination therapy with LHRH agonists and anti-androgens was associated with a significant increase in the risk of CHD (OR 4.35; 95% CI 1.94, 9.75), AMI (OR 3.57; 95% CI 1.44, 8.86), incident HF (OR 3.19; 95% CI 1.10, 9.27) and hospitalized HF (OR 3.39; 95% CI 1.07, 10.70) compared with non-use of these drugs.Conclusions: In men with prostate cancer, combination therapy with LHRH agonists and anti-androgens is associated with significant increases in the risk of CHD, AMI, incident HF and hospitalized HF. Individual therapies do not appear to increase the risk of these outcomes. [ABSTRACT FROM AUTHOR]

The authors have retracted the original article because it contains an error that has made the data unreliable. The authors have been invited to resubmit a revised version of the article. All authors agree to this retraction. [ABSTRACT FROM AUTHOR]