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.

Influenza Vaccination and Risk of Ischemic Stroke: A Population-Based Case-Control Study.

BACKGROUND AND OBJECTIVES: To assess the relationship between influenza vaccination in the general population and risk of a first ischemic stroke (IS) during pre-epidemic, epidemic and post-epidemic periods. METHODS: A nested case-control study was carried out in a Spanish primary care database over 2001-2015. Subjects aged 40-99 years with at-least 1-year registry and no history of stroke or cancer were selected to conform the source cohort, from which incident IS cases were identified and classified as cardioembolic or non-cardioembolic. Five controls per case were randomly selected, individually matched with cases for exact age, sex and date of stroke diagnosis (index date). 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. Adjusted odds ratios (AOR) and their respective 95% confidence intervals (CI) were computed through a conditional logistic regression. Pneumococcal vaccination was used as a negative control. RESULTS: From a cohort of 3,757,621 patients, we selected 14,322 incident IS cases (9,542 non-cardioembolic and 4,780 cardioembolic) and 71,610 matched controls. Of them, 41.4% and 40.5%, respectively, were vaccinated yielding a crude OR of 1.05(95%CI:1.01-1.10). Vaccinated subjects presented a higher prevalence of vascular risk factors, diseases and comedication than non-vaccinated and, after full adjustment, the association of influenza vaccination with IS yielded an AOR of 0.88(95%CI:0.84-0.92) was found, appearing early (AOR15-30 days=0.79;95%CI:0.69-0.92) and slightly declining over time (AOR>150 days=0.92;95%CI:0.87-0.98). A reduced risk of similar magnitude was observed with both types of IS, in the three epidemic periods and in all subgroups analyzed (men, women, subjects below and over 65 years of age, and subjects with intermediate and high vascular risk). By contrast, pneumococcal vaccination was not associated with a reduced risk of IS (AOR=1.08;95%CI:1.04-1.13). DISCUSSION: Results are compatible with a moderate protective effect of influenza vaccine on IS appearing early after vaccination. The finding that a reduced risk was also observed in pre-epidemic periods suggests that either the "protection" is not totally linked to prevention of influenza infection, or it may be partly explained by unmeasured confounding factors.

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.

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.

Trends in the use of oral anticoagulants, antiplatelets and statins in four European countries: a population-based study.

PURPOSE: To evaluate time trends in the prevalence of antithrombotic and statin use in four European countries. METHODS: Using population-based data from the United Kingdom, Denmark, Spain and Italy between 2010 and 2018, we calculated standardized annual prevalence proportions of antithrombotics and statin use, and changes in prevalence proportions (2018 vs. 2010). RESULTS: Prevalence proportion of statins increased from 24.8% to 24.6% (UK), 21.0% to 22.3% (Region of Southern Denmark [RSD]), 12.9% to 14.3% (Udine, Italy), and 20.3% to 23.2% (Spain). Prevalence proportions of antithrombotics declined in all four countries: 18.7% to 15.9% (UK; - 2.8% points), 18.9% to 18.1% (RSD; - 0.8% points), 17.7% to 16.6% (Udine; - 1.1% points) and 15.0% to 13.6% (Spain; - 1.4% points). These declines were driven by reductions in low-dose aspirin use: 15.3% to 8.9% (UK; - 6.4% points), 16.3% to 9.5% (RSD; - 6.8% points), 13.5% to 11.6% (Udine; - 1.9% points), and 10.2% to 8.8% (Spain; - 1.4% points). In the UK, low-dose aspirin use declined from 9.1% to 4.3% (- 4.8% points) for primary CVD prevention, and from 49.6% to 36.9% (- 12.7% points) for secondary prevention. Oral anticoagulant use gradually increased but did not fully account for the decrease in low-dose aspirin use. CONCLUSIONS: Antithrombotic use in the UK, RSD, Udine and Spain declined between 2010 and 2018, driven by a reduction in use of low-dose aspirin that is not completely explained by a gradual increase in OAC use. Use of statins remained constant in the UK, and increased gradually in the RSD, Udine and Spain.

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.

Relationship Between Influenza, Temperature, and Type 1 Myocardial Infarction: An Ecological Time-Series Study.

Background Previous studies investigating the relationship of influenza with acute myocardial infarction (AMI) have not distinguished between AMI types 1 and 2. Influenza and cold temperature can explain the increased incidence of AMI during winter but, because they are closely related in temperate regions, their relative contribution is unknown. Methods and Results The temporal relationship between incidence rates of AMI with demonstrated culprit plaque (type 1 AMI) from the regional primary angioplasty network and influenza, adjusted for ambient temperature, was studied in Madrid region (Spain) during 5 influenza seasons (from June 2013 to June 2018). A time-series analysis with quasi-Poisson regression models and distributed lag-nonlinear models was used. The incidence rate of type 1 AMI according to influenza vaccination status was also explored. A total of 8240 cases of confirmed type 1 AMI were recorded. The overall risk ratio (RR) of type 1 AMI during epidemic periods, adjusted for year, month, and temperature, was 1.23 (95% CI, 1.03-1.47). An increase of weekly influenza rate of 50 cases per 100 000 inhabitants resulted in an RR for type 1 AMI of 1.16 (95% CI, 1.09-1.23) during the same week, disappearing 1 week after. When adjusted for influenza, a decrease of 1ºC in the minimum temperature resulted in an increase of 2.5% type 1 AMI. Influenza vaccination was associated with a decreased risk of type 1 AMI in subjects aged 60 to 64 years (RR, 0.58; 95% CI, 0.47-0.71) and ≥65 years (RR, 0.53; 95% CI, 0.49-0.57). Conclusions Influenza and cold temperature were both independently associated with an increased risk of type 1 AMI, whereas vaccination was associated with a reduced risk among older 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.

Differential effects of antidepressant subgroups on risk of acute myocardial infarction: A nested case-control study.

The primary objective of this study was to investigate the association between antidepressants use and the risk of acute myocardial infarction (AMI). METHODS: We conducted a nested case-control study using a primary care database over the period 2002-2015. From a cohort of patients aged 40-99 years, we identified incident AMI cases and randomly selected 5 controls per case, matched to cases for exact age, sex and index date. Exposure to antidepressants were categorised as current, recent, past and nonusers. Adjusted odds ratio (AOR) and 95% confidence interval (CI) were computed using conditional logistic regression to assess the association between the current use of different antidepressants subgroups and AMI as compared to nonuse. Dose and duration effects were explored. RESULTS: Totals of 24 155 incident AMI cases and 120 775 controls were included. The current use of antidepressants as a group was associated with a reduced risk (AOR = 0.86; 95% CI: 0.81-0.91), but mainly driven by selective serotonin reuptake inhibitors (AOR = 0.86; 95% CI:0.81-0.93). A reduced risk was also observed with trazodone (AOR = 0.76;95% CI: 0.64-0.91), and clomipramine (AOR = 0.62; 95% CI: 0.40-0.96), whereas no significant effect was observed with other antidepressants. A duration-dependent effect was suggested for selective serotonin reuptake inhibitors, trazodone and clomipramine, while there was no clear dose-dependency. CONCLUSION: This study suggests that current use of antidepressants interfering selectively with the reuptake of serotonin, and those antagonizing the 5-HT2A receptor, are associated with a decrease in AMI risk and should be the antidepressants of choice in patients at cardiovascular risk.

Olas de calor, temperatura ambiente y riesgo de infarto de miocardio: un estudio ecológico en la Comunidad de Madrid / Heat waves, ambient temperature, and risk of myocardial infarction: an ecological study in the Community of Madrid

INTRODUCCIÓN Y OBJETIVOS: Los episodios de calor extremo se asocian con una mayor morbimortalidad de los enfermos crónicos, pero su relación con el infarto de miocardio no está claramente establecida. El objetivo es analizar una posible relación entre la incidencia de infarto agudo de miocardio con elevación del segmento ST (IAMCEST) y la temperatura máxima, especialmente durante los periodos de alerta por ola de calor (PAOC). MÉTODOS: La población estudiada son los casos de IAMCEST confirmado registrados en Código Infarto Madrid entre junio de 2013 y junio de 2017. Se estimaron las razones de tasa de incidencia (RTI) ajustadas por tendencia y estacionalidad y sus IC95% asociadas con los PAOC y con la temperatura máxima, utilizando modelos de regresión de series temporales. RESULTADOS: Se incluyó a 6.465 casos de IAMCEST. En 66 días de PAOC hubo 212 casos y 1.816 casos durante los días de verano sin alerta (RTI=1,14; IC95%, 0,96-1,35). La tasa de incidencia mínima se observó con temperatura máxima de 18°C. Las temperaturas más cálidas no se asociaron con mayor incidencia (RTI=1,03; IC95%, 0,76-1,41); por el contrario, hubo un incremento significativo con las temperaturas más frías (RTI=1,25; IC95%, 1,02-1,54). No hubo modificación por sexo o edad. CONCLUSIONES: Durante los PAOC entre junio de 2013 y junio de 2017 en la Comunidad de Madrid, no se observó un aumento de la incidencia de IAMCEST, pero sí durante periodos de bajas temperaturas. No cabe esperar un mayor uso de los recursos sanitarios para el IAMCEST en periodos de calor extremo, pero sí durante los periodos fríos

INTRODUCTION AND OBJECTIVES: Episodes of extreme heat are associated with increased morbidity and mortality in chronically-ill patients but there is a need to clearly establish the relationship between extreme heat and myocardial infarction. The aim of this study was to analyze the relationship between the incidence of ST-segment elevation myocardial infarction (STEMI) and maximum temperature, in particular during heat wave alert periods (HWAP). METHODS: The population studied consisted of confirmed STEMI cases registered in the Infarction Code of the Community of Madrid between June 2013 and June 2017. Incidence rate ratios (IRR) adjusted for trend and seasonality and 95%CI were estimated using time series regression models. RESULTS: A total of 6465 cases of STEMI were included; 212 cases occurred during the 66-day period of HWAP and 1816 cases during the nonalert summer period (IRR, 1.14; 95%CI, 0.96-1.35). The minimum incidence rate was observed at the maximum temperature of 18°C. Warmer temperatures were not associated with a higher incidence (IRR,1.03; 95%CI, 0.76-1.41), whereas colder temperatures were significantly associated with an increased risk (IRR, 1.25; 95%CI, 1.02-1.54). No effect modification was observed by age or sex. CONCLUSIONS: We did not find an increased risk of STEMI during the 66 days of HWAP in the Community of Madrid between June 2013 and June 2017. However, an increased risk was found during colder temperatures. No extra health resources for STEMI management are required during periods of extreme heat, but should be considered during periods of cold weather

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).

Heat waves, ambient temperature, and risk of myocardial infarction: an ecological study in the Community of Madrid.

INTRODUCTION AND OBJECTIVES: Episodes of extreme heat are associated with increased morbidity and mortality in chronically-ill patients but there is a need to clearly establish the relationship between extreme heat and myocardial infarction. The aim of this study was to analyze the relationship between the incidence of ST-segment elevation myocardial infarction (STEMI) and maximum temperature, in particular during heat wave alert periods (HWAP). METHODS: The population studied consisted of confirmed STEMI cases registered in the Infarction Code of the Community of Madrid between June 2013 and June 2017. Incidence rate ratios (IRR) adjusted for trend and seasonality and 95%CI were estimated using time series regression models. RESULTS: A total of 6465 cases of STEMI were included; 212 cases occurred during the 66-day period of HWAP and 1816 cases during the nonalert summer period (IRR, 1.14; 95%CI, 0.96-1.35). The minimum incidence rate was observed at the maximum temperature of 18°C. Warmer temperatures were not associated with a higher incidence (IRR,1.03; 95%CI, 0.76-1.41), whereas colder temperatures were significantly associated with an increased risk (IRR, 1.25; 95%CI, 1.02-1.54). No effect modification was observed by age or sex. CONCLUSIONS: We did not find an increased risk of STEMI during the 66 days of HWAP in the Community of Madrid between June 2013 and June 2017. However, an increased risk was found during colder temperatures. No extra health resources for STEMI management are required during periods of extreme heat, but should be considered during periods of cold weather.

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.