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We test the robustness of the self-controlled risk interval (SCRI) design in a setting where time between doses may introduce time-varying confounding, using both negative control outcomes (NCOs) and quantitative bias analysis (QBA). All vaccinated cases identified from 5 European databases between 1 September 2020 and end of data availability were included. Exposures were doses 1-3 of the Pfizer, Moderna, AstraZeneca, and Janssen COVID-19 vaccines; outcomes were myocarditis and otitis externa (NCO). The SCRI used a 60-day control window and dose-specific 28-day risk windows, stratified by vaccine brand and adjusted for calendar time. The QBA included two scenarios: (i) baseline probability of the confounder was higher in the control window and (ii) vice versa. The NCO was not associated with any of the COVID-19 vaccine types or doses except Moderna dose 1 (IRR = 1.09, 95%CI 1.01-1.09). The QBA suggested even the strongest literature-reported confounder (COVID-19; RRmyocarditis = 18.3) could only explain away part of the observed effect from IRR = 3 to IRR = 1.40. The SCRI seems robust to unmeasured confounding in the COVID-19 setting, although a strong unmeasured confounder could bias the observed effect upward. Replication of our findings for other safety signals would strengthen this conclusion.
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INTRODUCTION: The aim of this study was to assess the possible extent of bias due to violation of a core assumption (event-dependent exposures) when using self-controlled designs to analyse the association between COVID-19 vaccines and myocarditis. METHODS: We used data from five European databases (Spain: BIFAP, FISABIO VID, and SIDIAP; Italy: ARS-Tuscany; England: CPRD Aurum) converted to the ConcePTION Common Data Model. Individuals who experienced both myocarditis and were vaccinated against COVID-19 between 1 September 2020 and the end of data availability in each country were included. We compared a self-controlled risk interval study (SCRI) using a pre-vaccination control window, an SCRI using a post-vaccination control window, a standard SCCS and an extension of the SCCS designed to handle violations of the assumption of event-dependent exposures. RESULTS: We included 1,757 cases of myocarditis. For analyses of the first dose of the Pfizer vaccine, to which all databases contributed information, we found results consistent with a null effect in both of the SCRI and extended SCCS, but some indication of a harmful effect in a standard SCCS. For the second dose, we found evidence of a harmful association for all study designs, with relatively similar effect sizes (SCRI pre = 1.99, 1.40 - 2.82; SCRI post 2.13, 95 %CI - 1.43, 3.18; standard SCCS 1.79, 95 %CI 1.31 - 2.44, extended SCCS 1.52, 95 %CI = 1.08 - 2.15). Adjustment for calendar time did not change these conclusions. Findings using all designs were also consistent with a harmful effect following a second dose of the Moderna vaccine. CONCLUSIONS: In the context of the known association between COVID-19 vaccines and myocarditis, we have demonstrated that two forms of SCRI and two forms of SCCS led to largely comparable results, possibly because of limited violation of the assumption of event-dependent exposures.
Subject(s)
COVID-19 , Myocarditis , Vaccines , Humans , COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Research Design , Vaccination/adverse effectsABSTRACT
Using 4 data-sources (Spain, Italy, United Kingdom) data and a 1:1 matched cohort study, we aimed to estimate vaccine effectiveness (VE) in preventing SARS-CoV-2 infections with hospitalisations (±30 days) and death (±56 days) in general population and clinical subgroups with homologous/heterologous booster schedules (Comirnaty-BNT and Spikevax-MOD original COVID-19 vaccines) by comparison with unboosted individuals, during Delta and beginning of Omicron variants. Hazard Ratio (HR, by Cox models) and VE ([1-HR]*100) were calculated by inverse probability weights. Between December 2020-February 2022, in adults without prior SARS-CoV-2 infection, we matched 5.5 million people (>1 million with immunodeficiency, 343,727 with cancer) with a booster (3rd) dose by considering doses 1 and 2 vaccine brands and calendar time, age, sex, region, and comorbidities (immunodeficiency, cancer, severe renal disease, transplant recipient, Down Syndrome). We studied booster doses of BNT and MOD administered after doses 1 and 2 with BNT, MOD, or Oxford-AstraZeneca during a median follow-up between 9 and 16 weeks. BNT or MOD showed VE ranging from 70 to 86% across data sources as heterologous 3rd doses, whereas it was 42-88% as homologous 3rd doses. Depending on the severity and available follow-up, 3rd-dose effectiveness lasted between 1 and 5 months. In people with immunodeficiency and cancer, protection across data sources was detected with both heterologous (VE = 54-83%) and homologous (VE = 49-80%) 3rd doses. Overall, both heterologous and homologous 3rd doses with BTN or MOD showed additional protection against the severe effects of SARS-CoV-2 infections for the general population and for patients at potentially high risk of severe COVID-19 (elderly, people with immunodeficiency and cancer) in comparison with two doses schemes during Delta or early Omicron periods. The early VE after vaccination may be due to less testing among vaccinated pairs and unknown confounders, deserving cautious interpretation. The VE wane over time needs further in-depth research to properly envisage when or whether a booster of those vaccines should be administered.
Subject(s)
COVID-19 , Neoplasms , Adult , Aged , Humans , COVID-19 Vaccines , Cohort Studies , COVID-19/prevention & control , SARS-CoV-2 , VaccinationABSTRACT
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.
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INTRODUCTION: Due to established teratogenicity of valproates, the EU risk minimisation measures (RMMs) with a pregnancy prevention programme (PPP) for valproate were updated in March 2018. OBJECTIVES: To investigate the effectiveness of the 2018 EU RMMs on valproate utilisation in five European countries/regions. METHODS: A multi-database, times series study of females of childbearing potential (12-55 years) was conducted using electronic medical records from five countries/regions (01.01.2010-31.12.2020): Denmark, Tuscany (Italy), Spain, the Netherlands, and the UK. Clinical and demographic information from each database was transformed to the ConcePTION Common Data Model, quality checks were conducted and a distributed analysis was performed using common scripts. Incident and prevalent use of valproate, proportion of discontinuers and switchers to alternative medicine, frequency of contraception coverage during valproate use, and occurrence of pregnancies during valproate exposure were estimated per month. Interrupted time series analyses were conducted to estimate the level or trend change in the outcome measures. RESULTS: We included 69,533 valproate users from 9,699,371 females of childbearing potential from the five participating centres. A significant decline in prevalent use of valproates was observed in Tuscany, Italy (mean difference post-intervention -7.7%), Spain (-11.3%), and UK (-5.9%) and a non-significant decline in the Netherlands (-3.3%), but no decline in incident use after the 2018 RMMs compared to the period before. The monthly proportion of compliant valproate prescriptions/dispensings with a contraceptive coverage was low (<25%), with an increase after the 2018 RMMs only in the Netherlands (mean difference post-intervention 12%). There was no significant increase in switching rates from valproates to alternative medicine after the 2018 intervention in any of the countries/regions. We observed a substantial number of concurrent pregnancies during valproate exposure, but with a declining rate after the 2018 RMMs in Tuscany, Italy (0.70 per 1000 valproate users pre- and 0.27 post-intervention), Spain (0.48 and 0.13), the Netherlands (0.34 and 0.00), and an increasing rate in UK (1.13 and 5.07). CONCLUSION: There was a small impact of the 2018 RMMs on valproate use in the studied European countries/regions. The substantial number of concurrent pregnancies with valproate exposure warrants a careful monitoring of implementation of the existing PPP for valproate in clinical practice in Europe, to see if there is any need for additional measures in the future.
Subject(s)
Contraception , Valproic Acid , Pregnancy , Female , Humans , Valproic Acid/adverse effects , Interrupted Time Series Analysis , Europe/epidemiology , Italy/epidemiologyABSTRACT
Background: Estimates of the association between COVID-19 vaccines and myo-/pericarditis risk vary widely across studies due to scarcity of events, especially in age- and sex-stratified analyses. Methods: Population-based cohort study with nested self-controlled risk interval (SCRI) using healthcare data from five European databases. Individuals were followed from 01/01/2020 until end of data availability (31/12/2021 latest). Outcome was first myo-/pericarditis diagnosis. Exposures were first and second dose of Pfizer, AstraZeneca, Moderna, and Janssen COVID-19 vaccines. Baseline incidence rates (IRs), and vaccine- and dose-specific IRs and rate differences were calculated from the cohort The SCRI calculated calendar time-adjusted IR ratios (IRR), using a 60-day pre-vaccination control period and dose-specific 28-day risk windows. IRRs were pooled using random effects meta-analysis. Findings: Over 35 million individuals (49·2% women, median age 39-49 years) were included, of which 57·4% received at least one COVID-19 vaccine dose. Baseline incidence of myocarditis was low. Myocarditis IRRs were elevated after vaccination in those aged < 30 years, after both Pfizer vaccine doses (IRR = 3·3, 95%CI 1·2-9.4; 7·8, 95%CI 2·6-23·5, respectively) and Moderna vaccine dose 2 (IRR = 6·1, 95%CI 1·1-33·5). An effect of AstraZeneca vaccine dose 2 could not be excluded (IRR = 2·42, 95%CI 0·96-6·07). Pericarditis was not associated with vaccination. Interpretation: mRNA-based COVID-19 vaccines and potentially AstraZeneca are associated with increased myocarditis risk in younger individuals, although absolute incidence remains low. More data on children (≤ 11 years) are needed.
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BACKGROUND: Previous studies have suggested a relationship between human papillomavirus vaccine and autoimmune diseases, including thyroiditis. Thus, we aimed to evaluate the risk of thyroiditis associated with HPV vaccination among girls using the Primary Care Database For Pharmacoepidemiological Research (BIFAP) in Spain. METHODS: In this retrospective cohort study, girls in BIFAP aged 9-18 years from 2007 to 2016, free of past thyroiditis and HPV vaccination, were included. Hazard Ratios (HRs; 95% CI) of thyroiditis were calculated within exposed periods (up to 2 years of vaccination) and post-exposed periods (from 2 years after vaccination onwards) compared with non-exposed periods, overall, by dose and by type of vaccine, adjusted for potential confounders collected at different times. In a post-hoc analysis, we moved back the thyroiditis date (30 days) as a theoretical delay in diagnosis. RESULTS: Out of the 388,411 girls included in the cohort, 153,924 were vaccinated against HPV and 480 thyroiditis (253 autoimmune) cases were identified (334 non-exposed; 103 exposed; 43 post-exposed). Adjusted HR was 1.18 [95% CI: 0.79-1.76] for exposed (1.25 [0.77-2.04] for bi- and 1.15 [0.76-1.76] for quadri-valent vaccines) and 1.26 [0.74-2.14] for post-exposed periods. HR was 1.50 [0.87-2.59] for the 1st dose, 1.13 [0.66-1.91] for the 2nd and 1.11 [0.71-1.72] for the 3rd one. When the diagnosis date was moved back, the risk was 1.14 [0.76-1.70] for exposed period, being 1.80 [0.86-3.76] and 1.40 [0.74-2.66] after 1st dose of bi- and quadri-valent, respectively. CONCLUSIONS: We did not observe an increased risk of thyroiditis following HPV vaccination (whether bi- or quadri-valent). Even though the point estimate was higher after 1st HPV vaccination dose than after subsequent doses, a dose-effect was not confirmed. Results remained similar after applying a lag time.
Subject(s)
Papillomavirus Infections , Papillomavirus Vaccines , Thyroiditis , Uterine Cervical Neoplasms , Cohort Studies , Female , Humans , Papillomavirus Infections/epidemiology , Papillomavirus Infections/prevention & control , Papillomavirus Vaccines/adverse effects , Retrospective Studies , Thyroiditis/chemically induced , Thyroiditis/epidemiology , Uterine Cervical Neoplasms/prevention & control , Vaccination/adverse effectsABSTRACT
BACKGROUND: Studies of the association of Guillain-Barré Syndrome (GBS) with papillomavirus vaccination (HPVv; scheduled from 2007) have provided contradicting results, probably due to the low frequency of this disease. We aimed at estimating that risk relative to non-vaccination among girls, by using the Spanish Primary Care Database for Pharmacoepidemiological Research (BIFAP). METHODS: A cohort study of girls aged 9-18 years during 2007-2016 free of GBS or HPVv was selected and followed up to GBS diagnosis. Follow-up time was divided by time-varying HPVv exposure and confounders. Crude Incidence rates (IR per 1,000,000 person-years (py)) and adjusted Hazard Ratios (HR) of GBS were estimated anytime after vaccination compared to non-exposed periods. HRs were also estimated for the first 90 days after HPVv (risk-window) and thereafter. RESULTS: Out of 388,849 girls, of which 154,255 were vaccinated, 6 'confirmed' GBS cases occurred during non-exposure periods (IR of 5.83 per million person-years; 95% CI: 2.62-12.97) and 3 'confirmed' cases anytime after vaccination (IR of 7.87; 95% CI: 2.54-24.39). The resulting adjusted HR anytime after vaccination was 1.24 (95% CI: 0.19-8.00). All three cases occurred after the risk window of 90 days with an HR of 1.77 (95% CI: 0.25-12.54) for post-exposure periods as compared with non-exposure. Since zero cases occurred during the risk window, no HR could be estimated for exposed periods. CONCLUSIONS: Incidences of GBS were in line with the range previously reported for young people, supporting the potential of BIFAP for performing studies on GBS. However, a lack of power may be present for quantifying the relative risk of such a rare disease after the vaccination among the study cohort, where we can only exclude an increased risk of 8-times relative to no vaccination.
Subject(s)
Guillain-Barre Syndrome , Influenza Vaccines , Papillomavirus Infections , Papillomavirus Vaccines , Adolescent , Cohort Studies , Female , Guillain-Barre Syndrome/chemically induced , Guillain-Barre Syndrome/epidemiology , Humans , Incidence , Papillomavirus Infections/complications , Papillomavirus Infections/epidemiology , Papillomavirus Infections/prevention & control , Papillomavirus Vaccines/adverse effects , Spain/epidemiology , VaccinationABSTRACT
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.
Subject(s)
Inflammatory Bowel Diseases , Papillomavirus Infections , Papillomavirus Vaccines , Chronic Disease , Cohort Studies , Female , Humans , Inflammatory Bowel Diseases/epidemiology , Inflammatory Bowel Diseases/etiology , Male , Papillomavirus Infections/epidemiology , Papillomavirus Infections/prevention & control , Papillomavirus Vaccines/adverse effects , Primary Health Care , Spain/epidemiology , Vaccination/adverse effectsABSTRACT
Objective: As for other auto-immune processes, thyroiditis is monitored after vaccinations. The aim was to estimate the baseline incidence of thyroiditis among girls, before investigating papillomavirus vaccination as a potential risk factor. Methods: Observational cohort study including girls aged 9-18 years and registered between 2002-2016 in the Spanish Primary Care Database for Pharmacoepidemiological Research. Girls were followed until a thyroiditis occurred, 19 years of age, left the cohort, died, or the study ended. Anonymized records were reviewed for diagnosis confirmation (endocrine discharge letter and/or free-text comments) in a random sample. Incidence rate (IR) per 105 person years (/105 py) was estimated. Results: The cohort numbered 480,169 girls, of whom 641 had a record of thyroiditis: 346 autoimmune thyroiditis; 17 thyroiditis of other types; and 278 unspecified. Incidence of recorded thyroiditis increased with age, from 23.96 at age 9 years to 47.91 at age 14 years, and stabilized around 31.06-34.43 among girls aged 15-18 years. Of the 98 records reviewed, 60.2% were 'confirmed' cases, 32.7% 'possible' and 7.1% were discarded. After correction for discarded cases, IR=20.83 'confirmed' cases, increasing to 32.12/105 py when 'confirmed' plus 'possible' cases were included. Between 2002-2005, incidences were lower (16.28 and 20.93 cases/105 py) than in the period 2007-2016 (21.17 and 33.78 cases/105 py) for 'confirmed' and 'confirmed' plus 'possible', respectively. Conclusion: Two-thirds of the recorded thyroiditis included confirmatory evidence. The incidence of thyroiditis among girls increased with age and in the later period, and remained stable among girls aged 15-18 years.
Subject(s)
Primary Health Care/statistics & numerical data , Thyroiditis/epidemiology , Adolescent , Age Factors , Child , Female , Humans , Incidence , Spain/epidemiology , Thyroiditis, Autoimmune/epidemiologyABSTRACT
PURPOSE: Inflammatory bowel disease (IBD) recording validation among girls in the Spanish Primary Care Database For Pharmacoepidemiological Research (BIFAP). METHODS: In this observational study, girls aged 9 to 18 years registered in BIFAP between 2002 and 2016, were followed up until there was a recorded IBD diagnosis or a referral to specialist indicating IBD. Anonymized profiles were reviewed to retrieve diagnosis confirmation (a positive colonoscopy or biopsy, specialist, or physician's comments mentioning the IBD diagnosis) or discarding (negative procedure results, alternative diagnosis, or family history). "possible" IBD were profiles missing that evidence, or had suspected IBD. The prescriptions of intestinal anti-inflammatory agents, azatioprine, and mercaptopurine were collected. The prevalence of IBD was estimated after review. RESULTS: Out of 480 634 girls, 323 had a first ever recorded IBD, of which, 37.8% (N = 122) were "confirmed" incident IBD diagnosis, 19.8% (N = 64) discarded and 38.7% (N = 125) "possible" IBD. Additionally, 12 IBD records (3.7%) referred to prevalent IBD. Prescriptions were recorded in 94.3% (confirmed), 63.2% (possible), 83.3% (prevalent), and 3.1% (discarded) IBD cases. Prevalence was 52.83 "confirmed" or 93.58/105 girls when "possible" IBD were added. CONCLUSIONS: For a third of the girls, the first recorded IBD included evidence confirming the diagnosis while most of those with missing evidence had treatment indicated for IBD. For research focused in sensitivity, an algorithm including "possible" plus "confirmed" episodes is recommended, whereas only "confirmed" to guarantee higher predictive value. Prevalence suggests that IBD is not a rare disease among girls.
Subject(s)
Inflammatory Bowel Diseases , Electronic Health Records , Female , Humans , Inflammatory Bowel Diseases/diagnosis , Inflammatory Bowel Diseases/epidemiology , Pharmacoepidemiology , Prevalence , Primary Health CareABSTRACT
OBJECTIVE: To evaluate the appropriateness of the initial prescribed daily dose of non-vitamin K antagonist oral anticoagulants (NOACs) according to label in patients with non-valvular atrial fibrillation (NVAF) in the UK. DESIGN: Population-based cross-sectional study. SETTING: UK primary care. POPULATION: 30 467 patients with NVAF and a first prescription for apixaban, dabigatran or rivaroxaban between January 2011 and December 2016. MAIN OUTCOME MEASURES: Percentage of patients prescribed a NOAC dose according to the European Union (EU) labels (appropriately dosed), and not according to the EU labels (inappropriately dosed-including both underdosed and overdosed patients); percentage of patients prescribed an initial NOAC dose according to renal function status. RESULTS: A total of 15 252 (50.1%) patients started NOAC therapy on rivaroxaban, 10 834 (35.6%) on apixaban and 4381 (14.4%) on dabigatran. Among patients starting NOAC therapy on rivaroxaban, 17.3% were eligible to receive a reduced dose compared with 12.8% of patients starting on apixaban and 53.8% of patients starting on dabigatran. The majority of patients were prescribed an appropriate dose according to the EU labels: apixaban 74.9 %, dabigatran, 74.4%; rivaroxaban, 84.2%. Underdosing occurred in 21.6% (apixaban), 8.7% (dabigatran), 9.1% (rivaroxaban). Overdosing was more frequent for dabigatran (16.9%) than for rivaroxaban (6.6%) or apixaban (3.5%). There was a trend towards dose reduction with increasing renal impairment. Among patients with severe renal impairment, the majority received a reduced dose NOAC: apixaban, 91.1%, dabigatran, 80.0%, rivaroxaban, 83.0%. CONCLUSION: Between 2011 and 2016, the majority of patients starting NOAC therapy in UK primary care were prescribed a daily dose in line with the approved EU drug label. Underdosing was more than twice as common among patients starting on apixaban than those starting on dabigatran or rivaroxaban. Research into the patient characteristics that may influence inappropriate underdosing of NOACs in UK primary care is warranted.
Subject(s)
Anticoagulants/administration & dosage , Atrial Fibrillation/complications , Dabigatran/administration & dosage , Pyrazoles/administration & dosage , Pyridones/administration & dosage , Rivaroxaban/administration & dosage , Stroke/etiology , Stroke/prevention & control , Administration, Oral , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , United KingdomABSTRACT
OBJECTIVES: Hypotension is of particular relevance for patients with heart failure (HF), since almost all HF drugs cause lowering of blood pressure (BP) and it is associated with a poor prognosis. We aimed to investigate hypotension incidence and risk factors in patients with incident HF in the UK. DESIGN: Retrospective cohort study including nested case-control analyses. SETTING: The Health Improvement Network UK primary care database. PARTICIPANTS: 18 677 adult patients with incident HF during 2000-2005 were followed and cases of hypotension (systolic BP ≤90 mm Hg) were identified. Controls were age-matched, sex-matched and date-matched to cases (1:2). PRIMARY AND SECONDARY OUTCOME MEASURES: We estimated hypotension incidence in the full study population and relevant subgroups (eg, sex and age). Potential risk factors for hypotension overall and for multiple versus single hypotensive episodes were evaluated using conditional logistic regression and unconditional regression models, respectively. RESULTS: During a mean follow-up of 3.31 years, 2565 patients (13.7%) developed hypotension. The incidence of hypotension was 3.17 cases per 100 patient years (95% confidence interval (CI): 3.05-3.30), and was markedly increased in women aged 18-39 years (n=32; 17.72 cases per 100 patient-years; 95% CI: 9.69-29.73). Hypotension risk factors included high healthcare utilisation (proxy measure for HF severity and general comorbidity; eg, ≥10 primary care physician visits versus none, odds ratio (OR): 2.29; 95% CI: 1.34-3.90), previous hypotensive episodes (OR: 2.32; 95% CI: 1.84-2.92), renal failure and use of aldosterone antagonists, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Risk factors identified for hypotension generally overlapped with those for multiple versus single hypotensive episodes. CONCLUSIONS: Hypotension occurs frequently in patients with incident HF. Our findings may help identify patients most likely to benefit from close BP monitoring. The increased incidence of hypotension in young women with HF requires investigation.
Subject(s)
Heart Failure/epidemiology , Hypotension/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Cardiovascular Agents/adverse effects , Case-Control Studies , Comorbidity , Databases, Factual , Female , General Practice/statistics & numerical data , Heart Failure/drug therapy , Humans , Hypotension/chemically induced , Hypotension/physiopathology , Incidence , Male , Middle Aged , Retrospective Studies , Risk Factors , United Kingdom/epidemiology , Young AdultSubject(s)
Drug Therapy, Combination/statistics & numerical data , Mortality/trends , Nursing Homes/organization & administration , Polypharmacy , Age Distribution , Aged , Aged, 80 and over , Cause of Death , Female , Health Status , Humans , Inappropriate Prescribing/prevention & control , Male , Risk Factors , SpainABSTRACT
BACKGROUND: Many patients on warfarin therapy often present with supratherapeutic international normalized ratio (INR) levels, resulting from the influence of several patient-specific factors, which have been associated with adverse outcomes. OBJECTIVE: This article aims to identify risk factors for over-anticoagulation (INR levels ≥4) in a cohort of patients taking warfarin. METHODS: A cohort of warfarin users aged 18 to 85 years from January 2005 to April 2013 was identified in The Health Improvement Network U.K. primary care database (N = 12,506). A random date was assigned to all patients within their eligible person-time (index date), and a nested case-control analysis was performed with individuals presenting a first episode of INR level ≥4 after the index date used as cases (N = 699) and patients with non-supratherapeutic INR values (≤3) as controls (N = 9,798). Using unconditional logistic regression models, odds ratios with 95% confidence intervals were calculated adjusted for potential confounders. Two sensitivity analyses were performed with alternative definitions of over-anticoagulation (INR levels ≥5 or > 3). RESULTS: Among the factors examined, the strongest predictors of over-anticoagulation were warfarin indication (in particular, valvular atrial fibrillation and valve replacement), renal failure (with the risk increasing steeply with decreasing estimated glomerular filtration rate), cancer, anaemia, respiratory infections treated with antibiotics, chronic obstructive pulmonary disease treated with ß2-agonists, polypharmacy (≥10 medications), low socio-economic status and residency in rural areas. Similar results were obtained when supratherapeutic levels were defined as INR ≥5 or, alternatively, as INR > 3. CONCLUSION: Predictors of supratherapeutic INR levels found in this study might help physicians identify patients where closer INR monitoring is warranted.
Subject(s)
Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Blood Coagulation/drug effects , Warfarin/adverse effects , Warfarin/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Anemia/therapy , Case-Control Studies , Databases, Factual , Female , Glomerular Filtration Rate , Humans , International Normalized Ratio , Male , Medical Overuse , Middle Aged , Neoplasms/therapy , Odds Ratio , Poverty , Primary Health Care/organization & administration , Pulmonary Disease, Chronic Obstructive/therapy , Regression Analysis , Renal Insufficiency/therapy , Respiratory Tract Infections/therapy , Rural Population , United Kingdom , Young AdultABSTRACT
OBJECTIVE: To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels. METHODS: Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between 2005 and 2013 (N = 121,962) was followed until the first qualifying prescription for the potential interacting drugs was evaluated. Sixteen sub-cohorts, one for each study drug, and a control sub-cohort of warfarin were ascertained. Short-term changes in INR levels were assessed by comparing INR values measured before and after initiation of the interacting drug with paired Student's t-test. We also evaluated the proportion of patients with INR values outside the therapeutic range (INR: 2-3). RESULTS: Miconazole use was associated with the highest mean increase in INR (+3.35), followed by amiodarone (+1.28), fluconazole (+0.79), metronidazole (+0.75) and nystatin (+0.65). After subtracting the natural INR variation observed in the control sub-cohort, supra-therapeutic levels (INR > 3) were found in 53.2% (miconazole), 45.5% (amiodarone), 23.3% (metronidazole), 23.2% (fluconazole) and 17.6% (nystatin) of patients initiating treatment with these drugs. Carbamazepine use was associated with a mean INR decrease of -0.63 and infra-therapeutic levels (INR < 2) were observed in 46.2% of patients initiating carbamazepine. For all other drugs, the change was small to moderate, in absolute INR units (+0.23 to +0.55) and in the proportion of patients with INR levels out of therapeutic range (<16%). CONCLUSIONS: Clinically potentially important interactions were observed in several study drugs. The majority of them, although confirmed, had little impact after adjusting for standard INR variability in the general population of warfarin users.
Subject(s)
Anticoagulants/administration & dosage , Drug Interactions , International Normalized Ratio , Warfarin/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Amiodarone/administration & dosage , Carbamazepine/administration & dosage , Databases, Factual , Female , Fluconazole/administration & dosage , Follow-Up Studies , Humans , Male , Miconazole/administration & dosage , Middle Aged , Nystatin/administration & dosage , Primary Health Care , Retrospective Studies , United Kingdom , Young AdultABSTRACT
Introducción. La polifarmacia en las personas mayores es el resultado de la interconexión de múltiples factores y un fenómeno muy común a pesar de los riesgos asociados. No son muchos los estudios de base poblacional realizados en España con el objetivo de medir su magnitud en este grupo de población. Material y métodos. Estudio descriptivo, transversal realizado con datos individualizados de individuos de 65 años o más, de ambos sexos, no institucionalizados, procedentes de las Encuestas Nacionales de Salud de España (ENSE) 2006 (N=7.835) y 2011/12 (N=5.896). Se estimó la prevalencia de polifarmacia (consumo de al menos 4 fármacos en las 2 semanas previas a la encuesta) para las 2 encuestas utilizadas, así como por sexo y grupos de edad, y las prevalencias de uso de los diferentes grupos de fármacos entre los mayores polimedicados. Resultados. La polifarmacia ocurrió en aproximadamente uno de cada 3 mayores en la ENSE 2006 (32,54%), fue significativamente superior en la ENSE 2011/12 (36,37%) (p<0,05) y mayor en ambos casos en mujeres que en hombres y entre los individuos de mayor edad (≥85años) respecto a los más jóvenes. En las 2 encuestas analizadas, los grupos de fármacos más usados fueron los analgésicos (ENSE 2006: 71,93%; ENSE 2011/12: 76,27%; p<0,05) y antihipertensivos (ENSE 2006: 70,26%; ENSE 2011/12: 78,10%; p<0,05). Conclusiones. La magnitud de la polifarmacia en mayores es considerable y una práctica creciente en el tiempo. Se hace necesario conocer esta práctica en mayor profundidad, identificando a aquellos mayores con un riesgo elevado de consumir múltiples fármacos de forma simultánea (AU)
Introduction. Polypharmacy in older people is the result of several inter-connected factors, and is very common despite the associated risks. Not many population-based studies have been conducted in Spain to ascertain the magnitude of polypharmacy in this population. Material and methods. A descriptive, cross-sectional study was conducted with individualised data for non-institutionalised older people (65 or older) of both sexes from the Spanish National Health Surveys (SNHS) 2006 (N=7,835) and 2011/12 (N=5,896). The prevalence of polypharmacy (use of 4 or more drugs within the 2 weeks preceding the survey) was ascertained for the 2 surveys used, as well as by sex and age groups. The prevalence of use of the different drug groups was also estimated in the elderly who used polypharmacy. Results. Polypharmacy occurred in about a third of the older people in the 2006 SNHS (32.54%), and was significantly higher in the 2011/12 SNHS (36.37%) (P<.05). In both surveys, the prevalence of polypharmacy was higher in women than men and among the older individuals (≥85 years) compared to the less old. The type of drugs most commonly used were analgesics (2006 SNHS: 71.93%, 2011/12 SNHS: 76.27%; P<.05), and antihypertensive drugs 2006 SNHS: 70.26%, 2011/12 SNHS: 78.10%; P<.05). Conclusions. The magnitude of polypharmacy is considerable in older people and increasing over time. Further research on this issue is needed to identify those individuals who are at higher risk of using multiple drugs concomitantly (AU)
Subject(s)
Humans , Male , Female , Middle Aged , Aged , Aged, 80 and over , Polypharmacy , Aged/statistics & numerical data , Frail Elderly/statistics & numerical data , Drug Therapy, Combination/trends , Pharmacovigilance , Health Services for the Aged/statistics & numerical data , Health Services for the Aged , Health Surveys/statistics & numerical data , National Health Systems , Spain/epidemiology , Cross-Sectional Studies/methods , Cross-Sectional Studies/statistics & numerical data , Drug MonitoringABSTRACT
INTRODUCTION: Polypharmacy in older people is the result of several inter-connected factors, and is very common despite the associated risks. Not many population-based studies have been conducted in Spain to ascertain the magnitude of polypharmacy in this population. MATERIAL AND METHODS: A descriptive, cross-sectional study was conducted with individualised data for non-institutionalised older people (65 or older) of both sexes from the Spanish National Health Surveys (SNHS) 2006 (N=7,835) and 2011/12 (N=5,896). The prevalence of polypharmacy (use of 4 or more drugs within the 2 weeks preceding the survey) was ascertained for the 2 surveys used, as well as by sex and age groups. The prevalence of use of the different drug groups was also estimated in the elderly who used polypharmacy. RESULTS: Polypharmacy occurred in about a third of the older people in the 2006 SNHS (32.54%), and was significantly higher in the 2011/12 SNHS (36.37%) (P<.05). In both surveys, the prevalence of polypharmacy was higher in women than men and among the older individuals (≥85 years) compared to the less old. The type of drugs most commonly used were analgesics (2006 SNHS: 71.93%, 2011/12 SNHS: 76.27%; P<.05), and antihypertensive drugs 2006 SNHS: 70.26%, 2011/12 SNHS: 78.10%; P<.05). CONCLUSIONS: The magnitude of polypharmacy is considerable in older people and increasing over time. Further research on this issue is needed to identify those individuals who are at higher risk of using multiple drugs concomitantly.
Subject(s)
Polypharmacy , Aged , Aged, 80 and over , Cross-Sectional Studies , Drug Utilization/statistics & numerical data , Female , Health Surveys , Humans , Male , SpainABSTRACT
BACKGROUND: Low-dose aspirin has proven effectiveness in secondary and primary prevention of cardiovascular events, but is also associated with an increased risk of major bleeding events. For primary prevention, this absolute risk must be carefully weighed against the benefits of aspirin; such assessments are currently limited by a lack of data from general populations. METHODS: Systematic searches of Medline and Embase were conducted to identify observational studies published between 1946 and 4 March 2015 that reported the risks of gastrointestinal (GI) bleeding or intracranial hemorrhage (ICH) with long-term, low-dose aspirin (75-325 mg/day). Pooled estimates of the relative risk (RR) for bleeding events with aspirin versus non-use were calculated using random-effects models, based on reported estimates of RR (including odds ratios, hazard ratios, incidence rate ratios and standardized incidence ratios) in 39 articles. FINDINGS: The incidence of GI bleeding with low-dose aspirin was 0.48-3.64 cases per 1000 person-years, and the overall pooled estimate of the RR with low-dose aspirin was 1.4 (95% confidence interval [CI]: 1.2-1.7). For upper and lower GI bleeding, the RRs with low-dose aspirin were 2.3 (2.0-2.6) and 1.8 (1.1-3.0), respectively. Neither aspirin dose nor duration of use had consistent effects on RRs for upper GI bleeding. The estimated RR for ICH with low-dose aspirin was 1.4 (1.2-1.7) overall. Aspirin was associated with increased bleeding risks when combined with non-steroidal anti-inflammatory drugs, clopidogrel and selective serotonin reuptake inhibitors compared with monotherapy. By contrast, concomitant use of proton pump inhibitors decreased upper GI bleeding risks relative to aspirin monotherapy. CONCLUSIONS: The risks of major bleeding with low-dose aspirin in real-world settings are of a similar magnitude to those reported in randomized trials. These data will help inform clinical judgements regarding the use of low-dose aspirin in prevention of cardiovascular events.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Aspirin/adverse effects , Gastrointestinal Hemorrhage/etiology , Intracranial Hemorrhages/etiology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Aspirin/therapeutic use , Cardiovascular Diseases/prevention & control , Clopidogrel , Databases, Factual , Gastrointestinal Hemorrhage/epidemiology , Humans , Incidence , Intracranial Hemorrhages/epidemiology , Observational Studies as Topic , Odds Ratio , Risk , Ticlopidine/analogs & derivatives , Ticlopidine/therapeutic useABSTRACT
BACKGROUND: Few studies have evaluated incidence rates and risk factors for heart failure hospitalization (HFH) and mortality starting at initial heart failure (HF) diagnosis. METHODS: Patients with a first ever recorded diagnosis of HF between January 2000 and December 2005 (N=3516) were identified from The Health Improvement Network primary care database and followed until April 2011 to identify HFHs (through linked hospitalization data) and deaths. HF patients were stratified by hospitalization status at HF diagnosis (start date), and hazard ratios (HRs) for HFH and death were estimated using Cox regression. Predictors of HF re-admission were identified by nested case-control analysis among patients hospitalized at start date, using patients with a new HFH during follow-up as cases and a set of age and sex matched controls. RESULTS: During a mean follow-up of 4.5years, 32% of incident HF patients (n=1119) had a HFH and 58.5% died (n=2056). Compared with patients not hospitalized at initial HF diagnosis (N=2759), a two-fold increased risk of HFH during follow-up, consistent over time, was seen in patients hospitalized at initial HF diagnosis (N=757); adjusted HR 2.14 (95% CI: (1.88-2.44). Major predictors of HFH were renal impairment, diabetes and prior HFH. Mortality rates were higher in HF patients hospitalized at initial HF diagnosis, but the major determinant of mortality was HFH during follow-up: HR 3.88 (95% CI: 3.53-4.26) irrespective of HFH status at initial diagnosis. CONCLUSION: Patients hospitalized at initial HF diagnosis or with a HFH thereafter are at high risk of worse outcomes.