Development and Validation of Case-Finding Algorithms for Digestive Cancer in the Spanish Healthcare Database BIFAP.

BACKGROUND: electronic health records (EHRs) are helpful tools in epidemiology despite not being primarily collected for research. In Spain, primary care physicians play a central role and manage patients even in specialized care. All of this introduces variability that may lead to diagnostic inconsistencies. Therefore, data validation studies are crucial, so we aimed to develop and validate case-finding algorithms for digestive cancer in the primary care database BIFAP. METHODS: from 2001 to 2019, subjects aged 40-89 without a cancer history were included. Case-finding algorithms using diagnostic codes and text-mining were built. We randomly sampled, clustered, and manually reviewed 816 EHRs. Then, positive predictive values (PPVs) and 95% confidence intervals (95% CIs) for each cancer were computed. Age and sex standardized incidence rates (SIRs) were compared with those reported by the National Cancer Registry (REDECAN). RESULTS: we identified 95,672 potential cases. After validation, the PPV (95% CI) for hepato-biliary cancer was 87.6% (81.8-93.4), for esophageal cancer, it was 96.2% (93.1-99.2), for pancreatic cancer, it was 89.4% (84.5-94.3), for gastric cancer, it was 92.5% (88.3-96.6), and for colorectal cancer, it was 95.2% (92.1-98.4). The SIRs were comparable to those reported by the REDECAN. CONCLUSIONS: the case-finding algorithms demonstrated high performance, supporting BIFAP as a suitable source of information to conduct epidemiologic studies of digestive cancer.

Normative Data for Macular Thickness and Volume for Optical Coherence Tomography in a Diabetic Population without Maculopathies.

PURPOSE: The purpose was to establish normative data for the macular thicknesses and volume using spectral-domain optical coherence tomography (SD-OCT) in a diabetic population without maculopathies for use as a reference in diabetic retinopathy (DR) and diabetic macular edema screening programs. METHODS: This was an observational study nested in a cohort of diabetics from a telemedicine DR screening program. Each patient underwent SD-OCT centered on the fovea. Macular thickness and volume were described and compared using the built-in normative database of the device. Quantile regression models for the 97.5% percentile were fitted to evaluate the predictors of macular thickness and volume. RESULTS: A total of 3410 eyes (mean age, 62.25 (SD, 0.22) years) were included. Mean (SD) central subfield thickness (CST) was 238.2 (23.7) µm, while center thickness (CT), average thickness (AT), and macular volume (MV) were 205.4 (31.6) µm, 263.9 (14.3) µm, and 7.46 (0.40) mm3, respectively. Para- and perifoveal thicknesses were clinically and statistically significantly thinner in our population than in the normative reference database. The 97.5% percentile of the thickness of all sectors was increased in males and in the para- and perifovea among those with DR. CONCLUSIONS: All ETDRS sectors were thinner in patients with diabetes than in the reference population, except for the CST, which was the most stable parameter that only changed with sex. The upper cutoff limit to detect diabetic macular edema (DME) was different from that of the reference population and was influenced by conditions related to diabetes, such as DR. Therefore, specific normative data for diabetic patients should be used for the screening and diagnosis of DME using SD-OCT.

Risk of Ischemic Stroke Associated with Calcium Supplements and Interaction with Oral Bisphosphonates: A Nested Case-Control Study.

Conflicting results about the association of calcium supplements (CS) with ischemic stroke (IS) have been reported. We tested this hypothesis by differentiating between CS alone (CaM) and CS with vitamin D (CaD) and between cardioembolic and non-cardioembolic IS. We examined the potential interaction with oral bisphosphonates (oBs). A nested case-control study was carried out. We identified incident IS cases aged 40-90 and randomly sampled five controls per case matched by age, sex, and index date. Current users were compared to non-users. An adjusted odds ratios (AOR) and 95% CI were computed through conditional logistic regression. Only new users were considered. We included 13,267 cases (4400 cardioembolic, 8867 non-cardioembolic) and 61,378 controls (20,147 and 41,231, respectively). CaM use was associated with an increased risk of cardioembolic IS (AOR = 1.88; 95% CI: 1.21-2.90) in a duration-dependent manner, while it showed no association with non-cardioembolic IS (AOR = 1.05; 95% CI: 0.74-1.50); its combination with oBs increased the risk of cardioembolic IS considerably (AOR = 2.54; 95% CI: 1.28-5.04), showing no effect on non-cardioembolic. CaD use was not associated with either cardioembolic (AOR = 1.08; 95% CI: 0.88-1.31) or non-cardioembolic IS (AOR = 0.98; 95% CI: 0.84-1.13) but showed a small association with cardioembolic IS when combined with oBs (AOR = 1.35; 95% CI: 1.03-1.76). The results support the hypothesis that CS increases the risk of cardioembolic IS, primarily when used concomitantly with oBs.

Association of oral bisphosphonates with cardioembolic ischemic stroke: a nested case-control study.

Background: Bisphosphonates have been reported to increase the risk of atrial fibrillation. Therefore, it is conceivable that they may increase the risk of cardioembolic ischemic stroke (IS). However, most epidemiological studies carried out thus far have not shown an increased risk of IS, though none separated by the main pathophysiologic IS subtype (cardioembolic and non-cardioembolic) which may be crucial. In this study, we tested the hypothesis that the use of oral bisphosphonates increases specifically the risk of cardioembolic IS, and explored the effect of treatment duration, as well as the potential interaction between oral bisphosphonates and calcium supplements and anticoagulants. Methods: We performed a case-control study nested in a cohort of patients aged 40-99 years, using the Spanish primary healthcare database BIFAP, over the period 2002-2015. Incident cases of IS were identified and classified as cardioembolic or non-cardioembolic. Five controls per case were randomly selected, matched for age, sex, and index date (first recording of IS) using an incidence-density sampling. The association of IS (overall and by subtype) with the use of oral bisphosphonates within the last year before index date was assessed by computing the adjusted odds ratios (AOR) and their 95% CI using a conditional logistic regression. Only initiators of oral bisphosphonates were considered. Results: A total of 13,781 incident cases of IS and 65,909 controls were included. The mean age was 74.5 (SD ± 12.4) years and 51.6% were male. Among cases, 3.15% were current users of oral bisphosphonates, while among controls they were 2.62%, yielding an AOR of 1.15 (95% CI:1.01-1.30). Of all cases, 4,568 (33.1%) were classified as cardioembolic IS (matched with 21,697 controls) and 9,213 (66.9%) as non-cardioembolic IS (matched with 44,212 controls) yielding an AOR of 1.35 (95% CI:1.10-1.66) and 1.03 (95% CI: 0.88-1.21), respectively. The association with cardioembolic IS was clearly duration-dependent (AOR≤1 year = 1.10; 95% CI:0.82-1.49; AOR>1-3 years = 1.41; 95% CI:1.01-1.97; AOR>3 years = 1.81; 95% CI:1.25-2.62; p for trend = 0.001) and completely blunted by anticoagulants, even in long-term users (AOR>1 year = 0.59; 0.30-1.16). An interaction between oral bisphosphonates and calcium supplements was suggested. Conclusion: The use of oral bisphosphonates increases specifically the odds of cardioembolic IS, in a duration-dependent manner, while leaves materially unaffected the odds of non-cardioembolic IS.

EVALUATION OF THE INCLUSION OF SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY IN A TELEMEDICINE DIABETIC RETINOPATHY SCREENING PROGRAM: A Real Clinical Practice.

PURPOSE: To evaluate whether combining spectral domain optical coherence tomography with monoscopic fundus photography using a nonmydriatic camera (MFP-NMC) improves the accuracy of diabetic macular edema (DME) referrals in a teleophthalmology diabetic retinopathy screening program. METHODS: We conducted a cross-sectional study with all diabetic patients aged 18 years or older who attended screening from September 2016 to December 2017. We assessed DME according to the three MFP-NMC and the four spectral domain optical coherence tomography criteria. The sensitivity and specificity obtained for each criterion were estimated by comparing them with the ground truth of DME. RESULTS: This study included 3,918 eyes (1,925 patients; median age, 66 years; interquartile range, 58-73; females, 40.7%; once-screened, 68.1%). The prevalence of DME ranged from 1.22% to 1.83% and 1.54% to 8.77% on MFP-NMC and spectral domain optical coherence tomography, respectively. Sensitivity barely reached 50% in MFP-NMC and less for the quantitative criteria of spectral domain optical coherence tomography. When macular thickening and anatomical signs of DME were considered, sensitivity increased to 88.3% and the false DMEs and non-gradable images were reduced. CONCLUSION: Macular thickening and anatomical signs showed the highest suitability for screening, with a sensitivity of 88.3% and a specificity of 99.8%. Notably, MFP-NMC alone missed half of the true DMEs that lacked indirect signs.

Risk of ischaemic stroke among new users of glucosamine and chondroitin sulphate: a nested case-control study.

Background: Several studies have reported that the use of chondroitin sulphate (CS) and glucosamine may reduce the risk of acute myocardial infarction. Although it is thought that this potential benefit could be extended to ischaemic stroke (IS), the evidence is scarce. Objective: To test the hypothesis that the use of prescription glucosamine or CS reduces the risk of IS. Design: Case-control study nested in an open cohort. Methods: Patients aged 40-99 years registered in a Spanish primary healthcare database (BIFAP) during the 2002-2015 study period. From this cohort, we identified incident cases of IS, applying a case-finding algorithm and specific validation procedures, and randomly sampled five controls per case, individually matched with cases by exact age, gender and index date. Adjusted odds ratios (AORs) and 95% confidence interval (CI) were computed through a conditional logistic regression. Only new users of glucosamine or CS were considered. Results: A total of 13,952 incident cases of IS and 69,199 controls were included. Of them, 106 cases (0.76%) and 803 controls (1.16%) were current users of glucosamine or CS at index date, yielding an AOR of 0.66 (95% CI: 0.54-0.82) (for glucosamine, AOR: 0.55; 95% CI: 0.39-0.77; and for CS, AOR: 0.77; 95% CI: 0.60-0.99). The reduced risk among current users was observed in both sexes (men, AOR: 0.69; 95% CI: 0.49-0.98; women, AOR: 0.65; 95% CI: 0.50-0.85), in individuals above and below 70 years of age (AOR: 0.69; 95% CI: 0.53-0.89 and AOR: 0.59; 95% CI: 0.41-0.85, respectively), in individuals with vascular risk factors (AOR: 0.53; 95% CI: 0.39-0.74) and among current/recent users of nonsteroidal anti-inflammatory drugs (NSAIDs) (AOR: 0.71; 95% CI: 0.55-0.92). Regarding duration, the reduced risk was observed in short-term users (<365 days, AOR: 0.61; 95% CI: 0.48-0.78) while faded and became nonsignificant in long-term users (>364 days AOR: 0.86; 95% CI: 0.57-1.31). Conclusions: Our results support a protective effect of prescription CS and glucosamine in IS, which was observed even in patients at vascular risk. Mini abstract: Our aim was to analyse whether the use of glucosamine or chondroitin sulphate (CS) reduces the risk of ischaemic stroke (IS). We detected a significant decrease.

Statins and Colorectal Cancer Risk: A Population-Based Case-Control Study and Synthesis of the Epidemiological Evidence.

(1) Background: The pleiotropic effects of statins may explain a chemoprotective action against colorectal cancer (CRC). Many studies have tested this hypothesis, but results have been inconsistent so far. Moreover, few have examined statins individually which is important for determining whether there is a class effect and if lipophilicity and intensity may play a role. (2) Methods: From 2001-2014, we carried out a study comprised of 15,491 incident CRC cases and 60,000 matched controls extracted from the primary healthcare database BIFAP. We fit a logistic regression model to compute the adjusted-odds ratios (AOR) with their 95% confidence intervals (CIs). Additionally, we carried out a systematic review and meta-analysis. (3) Results: Current use of statins showed a reduced risk of CRC (AOR = 0.87; 95% CI: 0.83-0.91) not sustained after discontinuation. The association was time-dependent, starting early (AOR6months-1year = 0.85; 95% CI: 0.76-0.96) but weakened beyond 3-years. A class effect was suggested, although only significant for simvastatin and rosuvastatin. The risk reduction was more marked among individuals aged 70 or younger, and among moderate-high intensity users. Forty-eight studies were included in the meta-analysis (pooled-effect-size = 0.90; 95% CI: 0.86-0.93). (4) Conclusions: Results from the case-control study and the pooled evidence support a moderate chemoprotective effect of statins on CRC risk, modified by duration, intensity, and age.

Selective Serotonin Reuptake Inhibitors and Risk of Noncardioembolic Ischemic Stroke: A Nested Case-Control Study.

BACKGROUND: Multiple studies have reported that the use of selective serotonin reuptake inhibitors (SSRIs) is associated with an increased risk of ischemic stroke; however, this finding may be the result of a confounding by indication. We examined the association using different approaches to minimize such potential bias. METHODS: A nested case-control study was carried out in a Spanish primary health-care database over the study period 2001 to 2015. Cases were patients sustaining an ischemic stroke with no sign of cardioembolic or unusual cause. For each case, up to 5 matched controls (for exact age, sex, and index date) were randomly selected. Antidepressants were divided in 6 pharmacological subgroups according to their mechanism of action. The current use of SSRIs (use within a 30-day window before index date) was compared with nonuse, past use (beyond 365 days) and current use of other antidepressants through a conditional logistic regression model to obtain adjusted odds ratios and 95% CI. Only initiators of SSRIs and other antidepressants were considered. RESULTS: A total of 8296 cases and 37 272 matched controls were included. Of them, 255 (3.07%) were current users of SSRIs among cases and 834 (2.24%) among controls, yielding an adjusted odds ratio of 1.14 (95% CI, 0.97-1.34) as compared with nonusers, 0.94 (95% CI, 0.77-1.13) as compared with past-users and 0.74 (95% CI, 0.58-0.93) as compared with current users of other antidepressants. No relevant differences were found by duration (≤1, >1 year), sex, age (<70, ≥70 years old) and background vascular risk. CONCLUSIONS: The use of SSRIs was not associated with an increased risk of noncardioembolic ischemic stroke. On the contrary, as compared with other antidepressants, SSRIs appeared to be protective.

Influenza vaccine and risk of acute myocardial infarction in a population-based case-control study.

OBJECTIVE: To assess the relationship between influenza vaccination and risk of a first acute myocardial infarction (AMI) in the general population by different epidemic periods. METHODS: This is a population-based case-control study carried out in BIFAP (Base de datos para la investigación farmacoepidemiológica en atención primaria), over 2001-2015, in patients aged 40-99 years. Per each incident AMI case, five controls were randomly selected, individually matched for exact age, sex and index date (AMI diagnosis). A patient was considered vaccinated when he/she had a recorded influenza vaccination at least 14 days before the index date within the same season. The association between influenza vaccination and AMI risk was assessed through a conditional logistic regression, computing adjusted ORs (AOR) and their respective 95% CIs. The analysis was performed overall and by each of the three time epidemic periods per study year (pre-epidemic, epidemic and postepidemic). RESULTS: We identified 24 155 AMI cases and 120 775 matched controls. Of them, 31.4% and 31.2%, respectively, were vaccinated, yielding an AOR of 0.85 (95% CI 0.82 to 0.88). No effect modification by sex, age and background cardiovascular risk was observed. The reduced risk of AMI was observed shortly after vaccination and persisted over time. Similar results were obtained during the pre-epidemic (AOR=0.87; 95% CI 0.79 to 0.95), epidemic (AOR=0.89; 95% CI 0.82 to 0.96) and postepidemic (AOR=0.83; 95% CI 0.79 to 0.87) periods. No association was found with pneumococcal vaccine (AOR=1.10; 95% CI 1.06 to 1.15). CONCLUSIONS: Results are compatible with a moderate protective effect of influenza vaccine on AMI in the general population, mostly in primary prevention, although bias due to unmeasured confounders may partly account for the results.

Risk of acute myocardial infarction among new users of chondroitin sulfate: A nested case-control study.

OBJECTIVE: To test the hypothesis that the use of chondroitin sulfate (CS) or glucosamine reduces the risk of acute myocardial infarction (AMI). DESIGN: Case-control study nested in a primary cohort of patients aged 40 to 99 years, using the database BIFAP during the 2002-2015 study period. From this cohort, we identified incident cases of AMI and randomly selected five controls per case, matched by exact age, gender, and index date. Adjusted odds ratios (AOR) and 95% confidence interval (CI) were computed through a conditional logistic regression. Only new users of CS or glucosamine were considered. RESULTS: A total of 23,585 incident cases of AMI and 117,405 controls were included. Of them, 89 cases (0.38%) and 757 controls (0.64%) were current users of CS at index date, yielding an AOR of 0.57 (95%CI: 0.46-0.72). The reduced risk among current users was observed in both short-term (<365 days, AOR = 0.58; 95%CI: 0.45-0.75) and long-term users (>364 days AOR = 0.56; 95%CI:0.36-0.87), in both sexes (men, AOR = 0.52; 95%CI:0.38-0.70; women, AOR = 0.65; 95%CI:0.46-0.91), in individuals over or under 70 years of age (AOR = 0.54; 95%CI:0.38-0.77, and AOR = 0.61; 95%CI:0.45-0.82, respectively) and in individuals at intermediate (AOR = 0.65; 95%CI:0.48-0.91) and high cardiovascular risk (AOR = 0.48; 95%CI:0.27-0.83), but not in those at low risk (AOR = 1.11; 95%CI:0.48-2.56). In contrast, the current use of glucosamine was not associated with either increased or decreased risk of AMI (AOR = 0.86; 95%CI:0.66-1.08). CONCLUSIONS: Our results support a cardioprotective effect of CS, while glucosamine seems to be neutral. The protection was remarkable among subgroups at high cardiovascular risk.

Impact of in-hospital discontinuation with angiotensin receptor blockers or converting enzyme inhibitors on mortality of COVID-19 patients: a retrospective cohort study.

BACKGROUND: In the first wave of the COVID-19 pandemic, the hypothesis that angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) increased the risk and/or severity of the disease was widely spread. Consequently, in many hospitals, these drugs were discontinued as a "precautionary measure". We aimed to assess whether the in-hospital discontinuation of ARBs or ACEIs, in real-life conditions, was associated with a reduced risk of death as compared to their continuation and also to compare head-to-head the continuation of ARBs with the continuation of ACEIs. METHODS: Adult patients with a PCR-confirmed diagnosis of COVID-19 requiring admission during March 2020 were consecutively selected from 7 hospitals in Madrid, Spain. Among them, we identified outpatient users of ACEIs/ARBs and divided them in two cohorts depending on treatment discontinuation/continuation at admission. Then, they were followed-up until discharge or in-hospital death. An intention-to-treat survival analysis was carried out and hazard ratios (HRs), and their 95%CIs were computed through a Cox regression model adjusted for propensity scores of discontinuation and controlled by potential mediators. RESULTS: Out of 625 ACEI/ARB users, 340 (54.4%) discontinued treatment. The in-hospital mortality rates were 27.6% and 27.7% in discontinuation and continuation cohorts, respectively (HR=1.01; 95%CI 0.70-1.46). No difference in mortality was observed between ARB and ACEI discontinuation (28.6% vs. 27.1%, respectively), while a significantly lower mortality rate was found among patients who continued with ARBs (20.8%, N=125) as compared to those who continued with ACEIs (33.1%, N=136; p=0.03). The head-to-head comparison (ARB vs. ACEI continuation) yielded an adjusted HR of 0.52 (95%CI 0.29-0.93), being especially notorious among males (HR=0.34; 95%CI 0.12-0.93), subjects older than 74 years (HR=0.46; 95%CI 0.25-0.85), and patients with obesity (HR=0.22; 95%CI 0.05-0.94), diabetes (HR=0.36; 95%CI 0.13-0.97), and heart failure (HR=0.12; 95%CI 0.03-0.97). CONCLUSIONS: The discontinuation of ACEIs/ARBs at admission did not improve the in-hospital survival. On the contrary, the continuation with ARBs was associated with a trend to a reduced mortality as compared to their discontinuation and to a significantly lower mortality risk as compared to the continuation with ACEIs, particularly in high-risk patients.

Prevalencia de prescripción del ácido acetilsalicílico a dosis bajas en prevención primaria en población española, evolución temporal y factores asociados / Prescription prevalence of low dose aspirin in primary prevention in the Spanish population, trends over time and associated factors

ANTECEDENTES Y OBJETIVO: El uso del ácido acetilsalicílico a dosis bajas (AAS-DB) en prevención primaria es motivo de controversia, pero se desconoce su magnitud en España. El objetivo del estudio fue estimar la proporción de pacientes a los que se prescribió AAS-DB como prevención primaria durante el periodo 2002-2015 e identificar sus características. MÉTODOS: En una muestra de la base de datos de atención primaria para la investigación farmacoepidemiológica (BIFAP) se obtuvo la proporción de personas con prescripciones de AAS-DB, excluyendo los pacientes con enfermedad vascular oclusiva, fibrilación auricular y cáncer. Las proporciones se estandarizaron para la población española de 40-99 años. Se construyó un modelo de regresión logística para identificar los factores asociados a la prescripción de AAS-DB y se estimó su prevalencia según la combinación de dichos factores. RESULTADOS: Se incluyeron 102.850 sujetos, 6.198 de ellos usuarios de AAS-DB. La prevalencia estandarizada fue del 2,21% al comienzo del periodo y del 3,57% al final. La prescripción aumentó con la edad. Los factores más asociados fueron diabetes (OR=3,26; IC 95%: 3,07-3,47), dislipidemia (OR=2,08; 1,96-2,21), insuficiencia cardiaca (OR=2,02; 1,72-2,37) e hipertensión (OR=1,78; 1,67-1,90). La prevalencia de prescripción de AAS-DB alcanzó el 33,7% en mayores de 70 años con diabetes, hipertensión y dislipidemia. CONCLUSIONES: En el periodo estudiado la prescripción de AAS-DB para prevención primaria en España fue baja en la población general, pero elevada en pacientes diabéticos mayores de 70 años con factores de riesgo adicionales. Después de años de controversia parece necesario adecuar el uso de este fármaco en prevención primaria a las recomendaciones actuales

BACKGROUND AND OBJECTIVE: The use of low-dose acetylsalicylic acid (LD-ASA) in primary prevention is a matter of controversy, but its magnitude is unknown in Spain. The aim of the study was to estimate the proportion of patients who are prescribed LD-ASA for primary prevention and to identify their characteristics. METHODS: In a sample from the primary care database BIFAP we obtained the proportion of persons with prescriptions of LD-ASA over the period 2002-2015, excluding patients with any previous record of occlusive vascular disease, atrial fibrillation or cancer. The proportions were standardized to the Spanish population aged 40-99 years old. We identified the factors associated with the use of LD-ASA through a logistic regression and estimated its prevalence of use according to the presence of such factors. RESULTS: The sample included 102,850 subjects; of which 6,198 were users of LD-ASA. The standardized prevalence of prescription was 2.21% at the start of the period and 3.57% at the end, and increased with age. The factors with the strongest associations were diabetes (OR=3.26; 95%CI: 3.07-3.47), dyslipidaemia (OR=2.08; 1.96-2.21), heart failure (OR=2.02; 1.72-2.37), and hypertension (OR=1.78; 1.67-1.90). Among diabetic patients older than 70 years with hypertension and dyslipidaemia, the prevalence of LD-ASA prescription was 33.7%. CONCLUSIONS: The prescription of LD-ASA for primary prevention in Spain over the study period was low in the general population, but high in older diabetic patients with additional risk factors. After years of controversy, it is time to realign the use of this drug in primary prevention according to recent guidelines

Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study.

BACKGROUND: Concerns have been raised about the possibility that inhibitors of the renin-angiotensin-aldosterone system (RAAS) could predispose individuals to severe COVID-19; however, epidemiological evidence is lacking. We report the results of a case-population study done in Madrid, Spain, since the outbreak of COVID-19. METHODS: In this case-population study, we consecutively selected patients aged 18 years or older with a PCR-confirmed diagnosis of COVID-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted between March 1 and March 24, 2020. As a reference group, we randomly sampled ten patients per case, individually matched for age, sex, region (ie, Madrid), and date of admission to hospital (month and day; index date), from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database, in its last available year (2018). We extracted information on comorbidities and prescriptions up to the month before index date (ie, current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with COVID-19. To minimise confounding by indication, the main analysis focused on assessing the association between COVID-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. We calculated odds ratios (ORs) and 95% CIs, adjusted for age, sex, and cardiovascular comorbidities and risk factors, using conditional logistic regression. The protocol of the study was registered in the EU electronic Register of Post-Authorisation Studies, EUPAS34437. FINDINGS: We collected data for 1139 cases and 11 390 population controls. Among cases, 444 (39·0%) were female and the mean age was 69·1 years (SD 15·4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1·98, 95% CI 1·62-2·41) and risk factors (1·46, 1·23-1·73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for COVID-19 requiring admission to hospital of 0·94 (95% CI 0·77-1·15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0·80, 0·64-1·00) or angiotensin-receptor blockers (1·10, 0·88-1·37). Sex, age, and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and COVID-19 requiring admission to hospital, whereas a decreased risk of COVID-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0·53, 95% CI 0·34-0·80). The adjusted ORs were similar across severity degrees of COVID-19. INTERPRETATION: RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19. FUNDING: Instituto de Salud Carlos III.

Prescription prevalence of low dose aspirin in primary prevention in the Spanish population, trends over time and associated factors. / Prevalencia de prescripción del ácido acetilsalicílico a dosis bajas en prevención primaria en población española, evolución temporal y factores asociados.

BACKGROUND AND OBJECTIVE: The use of low-dose acetylsalicylic acid (LD-ASA) in primary prevention is a matter of controversy, but its magnitude is unknown in Spain. The aim of the study was to estimate the proportion of patients who are prescribed LD-ASA for primary prevention and to identify their characteristics. METHODS: In a sample from the primary care database BIFAP we obtained the proportion of persons with prescriptions of LD-ASA over the period 2002-2015, excluding patients with any previous record of occlusive vascular disease, atrial fibrillation or cancer. The proportions were standardized to the Spanish population aged 40-99 years old. We identified the factors associated with the use of LD-ASA through a logistic regression and estimated its prevalence of use according to the presence of such factors. RESULTS: The sample included 102,850 subjects; of which 6,198 were users of LD-ASA. The standardized prevalence of prescription was 2.21% at the start of the period and 3.57% at the end, and increased with age. The factors with the strongest associations were diabetes (OR=3.26; 95%CI: 3.07-3.47), dyslipidaemia (OR=2.08; 1.96-2.21), heart failure (OR=2.02; 1.72-2.37), and hypertension (OR=1.78; 1.67-1.90). Among diabetic patients older than 70 years with hypertension and dyslipidaemia, the prevalence of LD-ASA prescription was 33.7%. CONCLUSIONS: The prescription of LD-ASA for primary prevention in Spain over the study period was low in the general population, but high in older diabetic patients with additional risk factors. After years of controversy, it is time to realign the use of this drug in primary prevention according to recent guidelines.

Risk of Myocardial Infarction Among New Users of Calcium Supplements Alone or Combined With Vitamin D: A Population-Based Case-Control Study.

A population-based case-control study was conducted to evaluate the risk of acute myocardial infarction among new users of calcium supplements either in monotherapy (CaM) or in combination with vitamin D (CaD). A total of 23,025 cases and 114,851 controls randomly sampled from the underlying cohort and matched with cases by age, sex, and index date were included. New users of CaM and CaD were categorized as current users, recent users, past users, and nonusers. We computed adjusted odds ratios (AORs) and their 95% confidence intervals (CIs) among current users as compared with nonusers through a conditional logistic regression. No increased risk was associated with CaM overall (59 cases (0.26%) and 273 controls (0.24%); AOR = 0.80; 95% CI 0.59-1.09), nor was it found in any of the conditions examined. Instead, the use of CaD was associated with a decreased risk (275 cases (1.19%) and 1,160 controls (1.45%); AOR = 0.78; 95% CI 0.67-0.90), dose and duration-dependent, and particularly evident in patients with a high cardiovascular risk (AOR = 0.59; 95% CI 0.43-0.81).

Risk of Acute Myocardial Infarction Among New Users of Allopurinol According to Serum Urate Level: A Nested Case-Control Study.

OBJECTIVES: To test the hypothesis that allopurinol reduces the risk of acute myocardial infarction (AMI) in hyperuricemic patients and to assess whether the effect is dependent on dose, duration and serum uric acid (SUA) level attained after treatment. METHODS: Nested case-control study over the period 2002-2015. From a cohort of patients aged 40-99 years old, we identified incident AMI cases and randomly selected five controls per case, matched for exact age, sex and index date. Adjusted odds ratios (AOR) and 95% CI were computed through unconditional logistic regression. Only new users of allopurinol were considered. RESULTS: A total of 4697 AMI cases and 18,919 controls were included. Allopurinol use was associated with a reduced risk of AMI mainly driven by duration of treatment (AOR ≥180 days = 0.71; 95% CI: 0.60-0.84). Among long-term users (≥180 days), the reduced risk was only observed when the SUA level attained was below 7 mg/dL (AOR<6 mg/dL = 0.64; 95% CI: 0.49-0.82; AOR6-7mg/dL = 0.64; 95%CI:0.48-0.84); AOR>7mg/dL = 1.04; 95% CI: 0.75-1.46; p for trend = 0.001). A dose-effect was observed but faded out once adjusted for the SUA level attained. The reduced risk of AMI occurred in both patients with gout and patients with asymptomatic hyperuricemia. CONCLUSIONS: The results confirm a cardioprotective effect of allopurinol which is strongly dependent on duration and SUA level attained after treatment.

Population-based case-control study: chemoprotection of colorectal cancer with non-aspirin nonsteroidal anti-inflammatory drugs and other drugs for pain control.

BACKGROUND: Inflammation and overexpression of cyclooxygenase-2 (COX-2) have been described to play a key role in the progression from nonpathologic intestinal mucosa to colorectal cancer (CRC). AIMS: To assess the chemoprotective effect of non-aspirin nonsteroidal anti-inflammatory drugs (NA-NSAIDs) under different patterns of use in a Mediterranean population and to explore the potential effect of symptomatic slow-acting drugs for osteoarthritis (SYSADOAs; chondroitin sulfate and glucosamine) and metamizole (or dipyrone), also reported to influence COX-2 activity. METHODS: We performed a case-control study nested in a cohort extracted from the primary care database, BIFAP. From 2001 to 2014, we included 15 491 incident cases and 60 000 random controls. To estimate the association between the drugs of interest and CRC, we built logistic regression models to compute the adjusted-odds ratios (AOR) and 95% confidence intervals (CI). RESULTS: NA-NSAIDs use was associated with a reduced risk of CRC (AOR = 0.67; 95% CI: 0.63-0.71) and increased linearly with duration of treatment (p for trend <0.001). The effect diminished upon discontinuation but persisted statistically significant up to 1 year. All individual NA-NSAIDs examined showed a decreased risk. The concomitant use of proton-pump inhibitors (PPI) had no impact on the protective effect of NA-NSAIDs; AORPPI + NSAID  = 0.64; 0.58-0.71. SYSADOA use was associated with a reduced risk (0.79; 0.69-0.90) but disappeared after the exclusion of NSAID users during the previous 1 or 3 years (0.85; 0.70-1.04 and 1.00; 0.76-1.31 respectively). Metamizole did not show a chemoprotective effect. CONCLUSIONS: NA-NSAID use is associated with a duration-dependent risk reduction of CRC not shared by SYSADOAs or metamizole.

Incidence of Stevens-Johnson syndrome/toxic epidermal necrolysis among new users of different individual drugs in a European population: a case-population study.

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.

Validation study of colorectal cancer diagnosis in the Spanish primary care database, BIFAP.

PURPOSE: To define and validate a case-finding algorithm to identify incident colorectal cancer (CRC) in the Spanish primary care database BIFAP. METHODS: All potential incident CRC cases recorded during the study period 2001 to 2014 among patients 20 to 89 years old were identified using a defined case-finding algorithm tailored to BIFAP database characteristics and based on codes plus text mining strategies. Potential CRC cases identified by the algorithm were classified into eight homogeneous groups according to recording characteristics. Random samples of 100 cases per group were obtained, and electronic medical records were manually reviewed by two independent researchers. Positive predictive values (PPVs) were estimated per each group and for the whole sample taking into account the stratified sampling. Standardized incidence rate (SIR) of CRC was estimated and compared with that reported by the National Cancer Registry. Negative predictive value (NPV) was also estimated in a random sample of 100 non-CRC patients by the algorithm. RESULTS: A total of 17 008 potential CRC cases were identified. Most of them (14793; 87%) were recorded as incident diagnosis with linked clinical notes as free text, having this group a PPV of 92.1% (95%CI: 87.1%-95.3%). The overall PPV including all groups was 87.3% (95%CI: 83.3%-90.4%). SIR of CRC was 55.5 per 100.000 person-years. SIR increased with age and was higher in men as compared with women (77.7 vs 38.1 per 100.000 py, respectively) which were in line with those reported by the Network of Cancer Registries in Spain. NPV was of 100% (96.3%-100%). CONCLUSIONS: This study shows a high validity of the CRC cases identified by the algorithm and a high level of CRC recording in BIFAP database and supports its appropriateness to validly identify incident CRC cases in BIFAP.

Clopidogrel and Low-Dose Aspirin, Alone or Together, Reduce Risk of Colorectal Cancer.

BACKGROUND & AIMS: The antiplatelet effect of low-dose aspirin, via inhibition of cyclooxygenase-1, might contribute to its ability to reduce the risk of colorectal cancer (CRC). Antiplatelet agents with a different mechanism, such as clopidogrel, might have the same effects. We aimed to quantify the effects of low-dose aspirin and clopidogrel on the risk of CRC in a Mediterranean population. METHODS: We performed a nested case-control study using a primary care database (Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria) in Spain. We collected data, from 2001 through 2014, on 15,491 incident cases of CRC and 60,000 randomly selected individuals (controls), frequency-matched to cases by age, sex, and year. To estimate the association between exposure to different antiplatelet agents and the risk of colorectal cancer, we built multiple logistic regression models and computed the adjusted-odds ratios (AORs) and their respective 95% CIs. RESULTS: Use of low-dose aspirin was associated with a reduced risk of CRC overall (AOR, 0.83; 95% CI, 0.78-0.89) and in patients receiving treatment for more than 1 year (AOR, 0.79; 95% CI, 0.73-0.85). Use of clopidogrel was associated with a decreased risk of CRC overall (AOR, 0.8; 95% CI, 0.69-0.93) and in patients receiving treatment for more than 1 year (AOR, 0.65; 95% CI, 0.55-0.78). Dual antiplatelet therapy had the same effect as either drug taken as monotherapy. No modification by sex or age was observed. CONCLUSIONS: In a nested case-control study of a primary care database in Spain, we found clopidogrel use, alone or in combination with low-dose aspirin, to reduce the risk of CRC by 20% to 30%, a magnitude similar to that of low-dose aspirin alone. These data support the concept that inhibiting platelets is an effective strategy for prevention of CRC.