Clinical pharmacology facing the real-world setting: Pharmacovigilance, pharmacoepidemiology and the economic evaluation of drugs.

Traditionally, clinical pharmacology has focused its activities on drug-organism interaction, from an individual or collective perspective. Drug efficacy assessment by performing randomized clinical trials and analysis of drug use in clinical practice by carrying out drug utilization studies have also been other areas of interest. From now on, Clinical pharmacology should move from the analysis of the drug-individual interaction to the analysis of the drug-individual-society interaction. It should also analyze the clinical and economic consequences of the use of drugs in the conditions of normal clinical practice, beyond clinical trials. The current exponential technological development that facilitates the analysis of real-life data offers us a golden opportunity to move to all these other areas of interest. This review describes the role that clinical pharmacology has played at the beginning and during the evolution of pharmacovigilance, pharmacoepidemiology and economic drug evaluations in Spain. In addition, the challenges that clinical pharmacology is going to face in the following years in these three areas are going to be outlined too.

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.

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.

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.

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.

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.

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.

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.

Active surveillance of severe cutaneous adverse reactions: A case-population approach using a registry and a health care database.

PURPOSE: The "case-population" design has been proposed for the surveillance of rare events like Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), wherein a registry of cases is combined with sales data from the source population in order to estimate crude odds ratios (ORs). A major drawback of this method is the inability to distinguish between new and non-new users of drugs, which for the study of hypersensitivity reactions is of utmost importance. METHODS: We have explored an approach in which the exposure to the drugs of interest in the source population is inferred from a primary health care database (BIFAP), which helped us to identify drug initiators among all users and additionally adjust for potential confounders. A total of 44 SJS/TEN cases from the Registry and 44 000 controls randomly sampled from BIFAP and matched with cases for index date were included. We estimated the adjusted ORs (AORs) and 95% confidence intervals (CI) of SJS/TEN associated with the new use of 13 drugs (for which we had at least two exposed cases) through a conditional logistic regression model. RESULTS: AORs (95% CI) were estimated for phenytoin, 4618 (434-49112); cotrimoxazole, 1142 (163-8015); allopurinol, 160 (36-709); dexamethasone, 38 (1.33-1077); ibuprofen, 33 (8.6-124); lorazepam, 27 (5.8-124); paracetamol, 13 (2.8-62); levofloxacine, 12 (1.24-120); amoxicillin, 6.9 (1.39-35); pantoprazole, 6.5 (0.10-420); metamizole, 6.3 (0.69-57); amoxicillin clavulanic acid, 4.2 (0.53-34); and omeprazole, 1.34 (0.06-31). The inclusion of non-new users dramatically decreased the AORs for all drugs. CONCLUSIONS: The case-population approach using a registry of cases and a primary health care database proved feasible and efficient for the active surveillance of SJS/TEN.

Significant HLA class I type associations with aromatic antiepileptic drug (AED)-induced SJS/TEN are different from those found for the same AED-induced DRESS in the Spanish population.

Aromatic antiepileptic drugs (AEDs) are among the drugs most frequently involved in severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). This study investigated the associations between the genetic polymorphisms of HLA class-I and AED-induced SCARs in the Spanish population. HLA class-I genotypes were determined in AED (phenytoin[PHT],lamotrigine[LTG],carbamazepine[CBZ],phenobarbital[PB])-induced SJS/TEN (n=15) or DRESS (n=12) cases included in the Spanish SCAR registry, PIELenRed. There were 3 control groups: (A)tolerant to a single AED, (B)tolerant to any AED, and (C)Spanish population controls. For SJS/TEN, concomitant HLA-A*02:01/Cw15:02 alleles were significantly associated with PHT-cases compared to control groups B and C [(B)odds ratio(OR):14.75, p=0.009;(C)OR:27.50, p<0.001], and were close to significance with respect to control group A (p=0.060). The genotype frequency of the HLA-B*38:01 was significantly associated with PHT-LTG-cases compared with the 3 groups of controls [(A)OR:12.86, p=0.012;(B)OR:13.81; p=0.002;(C)OR:14.35, p<0.001], and with LTG-cases [(A)OR:147.00, p=0.001;(B)OR:115.00, p<0.001;(C)OR:124.70, p<0.001]. We found the HLA-B*15:02 allele in a Spanish Romani patient with a CBZ-case. The HLA-A*11:01 was significantly associated with CBZ-cases [(A)OR:63.89, p=0.002;(B)OR:36.33, p=0.005;(C)OR:28.29, p=0.007]. For DRESS, the HLA-A*24:02 genotype frequency was statistically significant in the PHT-LTG-cases [(A)OR:22.56, p=0.003;(B)OR:23.50. p=0.001; (C)OR:33.25, p<0.001], and in the LTG-cases [(A),OR:49.00, p=0.015;(B)OR:27.77, p=0.005; (C)OR:34.53, p=0.002]. HLA-A*31:01 was significantly associated with the CBZ-cases [(A)OR:22.00, p=0.047;(B)OR:29.50, p=0.033;(C)OR:35.14, p=0.006]. In conclusion, we identified several significant genetic risk factors for the first time in the Spanish Caucasian population: HLA-A*02:01/Cw*15:02 combination as a risk factor for PHT-induced SJS/TEN, HLA-B*38:01 for LTG- and PHT- induced SJS/TEN, HLA-A*11:01 for CBZ-induced SJS/TEN, and HLA-A*24:02 for LTG- and PHT- induced DRESS. The strong association between HLA*31:01 and CBZ-DRESS in Europeans was confirmed in this study.

Hip/femur fractures associated with the use of benzodiazepines (anxiolytics, hypnotics and related drugs): a methodological approach to assess consistencies across databases from the PROTECT-EU project.

BACKGROUND: Results from observational studies may be inconsistent because of variations in methodological and clinical factors that may be intrinsically related to the database (DB) where the study is performed. OBJECTIVES: The objectives of this paper were to evaluate the impact of applying a common study protocol to study benzodiazepines (BZDs) (anxiolytics, hypnotics, and related drugs) and the risk of hip/femur fracture (HFF) across three European primary care DBs and to investigate any resulting discrepancies. METHODS: To measure the risk of HFF among adult users of BZDs during 2001-2009, three cohort and nested case control (NCC) studies were performed in Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) (Spain), Clinical Practice Research Datalink (CPRD) (UK), and Mondriaan (The Netherlands). Four different models (A-D) with increasing levels of adjustment were analyzed. The risk according to duration and type of BZD was also explored. Adjusted hazard ratios (cohort), odds ratios (NCC), and their 95% confidence intervals were estimated. RESULTS: Adjusted hazard ratios (Model C) were 1.34 (1.23-1.47) in BIFAP, 1.66 (1.54-1.78) in CPRD, and 2.22 (1.55-3.29) in Mondriaan in cohort studies. Adjusted odds ratios (Model C) were 1.28 (1.16-1.42) in BIFAP, 1.60 (1.49-1.72) in CPRD, and 1.48 (0.89-2.48) in Mondriaan in NCC studies. A short-term effect was suggested in Mondriaan, but not in CPRD or BIFAP. All DBs showed an increased risk with the concomitant use of anxiolytic and hypnotic drugs. CONCLUSIONS: Applying similar study methods to different populations and DBs showed an increased risk of HFF in BZDs users but differed in the magnitude of the risk, which may be because of inherent differences between DBs.

Risk of toxic epidermal necrolysis and Stevens-Johnson syndrome associated with benzodiazepines: a population-based cohort study.

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

Risk of nonfatal acute myocardial infarction associated with non-steroidal antiinflammatory drugs, non-narcotic analgesics and other drugs used in osteoarthritis: a nested case-control study.

PURPOSE: The purpose of this study is to estimate the risk of nonfatal acute myocardial infarction (AMI) associated with traditional NSAIDs (tNSAIDs), non-narcotic analgesics (paracetamol and metamizole), and symptomatic slow-acting drugs in osteoarthritis (SYSADOAs) overall and in different subgroups of patients. METHODS: We performed a nested case-control study using a Primary Care Database (Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria), over the study period, 2001-2007. We included patients aged 40-90 years, with nonfatal AMI and randomly selected controls matched for age, sex and calendar year. Exposure to drugs was assessed within a 30-day window before the index date. RESULTS: We did not find an association with nonfatal AMI in patients at low-intermediate background cardiovascular risk (odds ratio = 0.92; 95% confidence interval: 0.76-1.12), whereas there was a moderate significant association among those at high risk (1.28; 1.06-1.54) or when tNSAIDs were used for longer than 365 days (1.43; 1.12-1.82). The greatest risk occurred when these two conditions were combined (1.80; 1.26-2.58). The risk varied across individual tNSAIDs, with ibuprofen (0.95; 0.78-1.16) in the lower and aceclofenac (1.59; 1.15-2.19) in the upper part of the range. Low-dose aspirin did not modify the risk profile showed by any of the individual tNSAIDs examined. Paracetamol (0.84; 0.74-0.95), metamizole (1.06; 0.87-1.29) and SYSADOAs (0.68; 0.47-0.99) were not associated with an increased risk overall or in any subgroup of patients. CONCLUSIONS: The risk of nonfatal AMI varied with individual tNSAIDs, duration of treatment and background cardiovascular risk. Paracetamol, metamizole and SYSADOAs did not increase the risk in any of the conditions examined.

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.

Upper gastrointestinal bleeding associated with NSAIDs, other drugs and interactions: a nested case-control study in a new general practice database.

AIM: To test the ability a new Spanish primary care research database (BIFAP) to capture the association between upper gastrointestinal bleeding (UGIB) and NSAIDs and other drugs and compare the results with previous studies. METHODS: We performed a nested case-control study in persons aged 40-90 years old included in the period 2001-2005. Potential cases were selected through a computer search followed by an individual blinded review. Controls matched for age, sex and calendar year were randomly selected. The exposure window was defined as 0-30 days before the index date. Adjusted odds ratios were obtained through unconditional logistic regression models. RESULTS: In a study cohort of 669,115 subjects (1,576,442 person-years) we retrieved 1,193 valid incident cases. Increased risks were found with current use of NSAIDs (RR = 1.72; 95 %CI: 1.41-2.09), metamizole (1.52; 1.09-2.13), low-dose aspirin (1.74; 1.37-2.21), other antiplatelet drugs (1.73; 1.27-2.36), and oral anticoagulants (2.00; 1.44-2.77). We did not find an increased risk with current use of oral corticosteroids (1.11; 0.66-1.86), SSRIs (1.05; 0.77-1.42), or paracetamol (1.00; 0.82-1.23). Acid-suppressing drugs reduced the risk among users of NSAIDs (0.58; 0.39-0.85), particularly in users with antecedents of peptic ulcer (0.16; 0.05-0.58). We detected a decreasing time-trend in the relative risk and the population attributable proportion associated with NSAIDs over the study period. CONCLUSIONS: The increased risk of UGIB associated with NSAIDs was lower than previously reported, which could partly be explained by methodological differences, but a decreasing burden over time of this drug safety problem is suggested. BIFAP has shown to be a valuable tool for pharmacoepidemiological research.

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.