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Masso Gonzalez E.L.,Astrazeneca | Masso Gonzalez E.L.,Spanish Center for Pharmacoepidemiological Research | Patrignani P.,University of Chieti Pescara | Tacconelli S.,University of Chieti Pescara | Garcia Rodriguez L.A.,Spanish Center for Pharmacoepidemiological Research
Arthritis and Rheumatism | Year: 2010

Objective. Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk of upper gastrointestinal (GI) bleeding/perforation, but the magnitude of this effect for coxibs in the general population and the degree of variability between individual NSAIDs is still under debate. This study was undertaken to assess the risk of upper GI bleeding/perforation among users of individual NSAIDs and to analyze the correlation between this risk and the degree of inhibition of whole blood cyclooxygenase 1 (COX-1) and COX-2 in vitro. Methods. We conducted a systematic review of observational studies on NSAIDs and upper GI bleeding/perforation published between 2000 and 2008. We calculated pooled relative risk (RR) estimates of upper GI bleeding/perforation for individual NSAIDs. Additionally, we verified whether the degree of inhibition of whole blood COX-1 and COX-2 in vitro by average circulating concentrations predicted the RR of upper GI bleeding/perforation. Results. The RR of upper GI bleeding/perforation was 4.50 (95% confidence interval [95% CI] 3.82-5.31) for traditional NSAIDs and 1.88 (95% CI 0.96-3.71) for coxibs. RRs lower than that for NSAIDs overall were observed for ibuprofen (2.69 [95% CI 2.17-3.33]), rofecoxib (2.12 [95% CI 1.59-2.84]), aceclofenac (1.44 [95% CI 0.65-3.2]), and celecoxib (1.42 [95% CI 0.85-2.37]), while higher RRs were observed for ketorolac (14.54 [95% CI 5.87-36.04]) and piroxicam (9.94 [95% CI 5.99-16.50). Estimated RRs were 5.63 (95% CI 3.83-8.28) for naproxen, 5.57 (95% CI 3.94-7.87) for ketoprofen, 5.40 (95% CI 4.16-7.00) for indomethacin, 4.15 (95% CI 2.59-6.64) for meloxicam, and 3.98 (95% CI 3.36-4.72) for diclofenac. The degree of inhibition of whole blood COX-1 did not significantly correlate with RR of upper GI bleeding/perforation associated with individual NSAIDs (r2 = 0.34, P = 0.058), but a profound and coincident inhibition (>80%) of both COX isozymes was associated with higher risk. NSAIDs with a long plasma half-life and with a slow-release formulation were associated with a greater risk than NSAIDs with a short half-life. Conclusion. The results of our analysis demonstrate that risk of upper GI bleeding/perforation varies between individual NSAIDs at the doses commonly used in the general population. Drugs that have a long half-life or slow-release formulation and/or are associated with profound and coincident inhibition of both COX isozymes are associated with a greater risk of upper GI bleeding/perforation. © 2010, American College of Rheumatology.


de Abajo F.J.,University of Alcalá | Gil M.J.,Spanish Agency for Medicines and Medical Devices | Garcia Poza P.,University of Alcalá | Bryant V.,Spanish Agency for Medicines and Medical Devices | And 3 more authors.
Pharmacoepidemiology and Drug Safety | Year: 2014

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 40-90years, 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 365days (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. © 2014 John Wiley & Sons, Ltd.


De Abajo F.J.,University of Alcalá | Gil M.J.,Spanish Agency for Medicines and Medical Devices | Rodriguez A.,University of Alcalá | Garcia-Poza P.,University of Alcalá | And 3 more authors.
Heart | Year: 2015

Objectives To quantify the risk of non-fatal acute myocardial infarction (AMI) among users of allopurinol. Methods We carried out a population-based case-control study over the period 2001-2007 in patients aged 40-90 years. Patients who had prescriptions of allopurinol or an episode of AMI before the start date of follow-up were excluded from the main analysis. Allopurinol initiators were classified as current users if their last prescription ended in the 30-day window before the recorded date of AMI for cases and a random date for controls. The association between use of allopurinol and non-fatal AMI was measured through an OR and adjusted for confounding factors by an unconditional logistic regression. Results We identified 3171 cases of non-fatal AMI and 18 525 controls. Cases had a lower prevalence of current use of allopurinol (0.82%) than controls (1.03%), yielding to an OR of 0.52 (95% CI 0.33 to 0.83). The decreased risk was driven by men (OR in men=0.44; 95% CI 0.25 to 0.76; OR in women=0.90; 0.36 to 2.23). No difference by age was observed. The effect was only observed at higher doses (300 mg or greater OR=0.30; 0.13 to 0.72; <300 mg OR=0.67; 0.37 to 1.23) and with prolonged treatments (<31 days, OR=1.12 (0.55 to 2.29); 31-180 days, OR=0.61; 0.29 to 1.29; >180 days OR=0.21; 0.08 to 0.53; p for trend=0.001). Among those with a previous AMI, allopurinol use also showed a significant reduced risk of recurrence (OR=0.16; 0.04 to 0.76). Conclusions The present study supports the hypothesis that allopurinol is associated with a reduced risk of non-fatal AMI, which seems to be dose-dependent and duration-dependent.


De Abajo F.J.,Spanish Agency for Medicines and Medical Devices | De Abajo F.J.,University Hospital Principe Of Asturias | De Abajo F.J.,University of Alcalá | Gil M.J.,Spanish Agency for Medicines and Medical Devices | And 4 more authors.
European Journal of Clinical Pharmacology | Year: 2013

Summary: 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. © 2012 Springer-Verlag.


Garcia-Poza P.,University of Alcalá | de Abajo F.J.,University of Alcalá | Gil M.J.,Spanish Agency for Medicines and Medical Devices | Chacon A.,Madrid Health Service | And 2 more authors.
Journal of Thrombosis and Haemostasis | Year: 2015

To assess the risk of non-fatal ischemic stroke associated with non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol. The effects of dose, duration of treatment, background cardiovascular (CV) risk and use of concomitant aspirin were studied. Methods: We performed a population-based case-control study. Patients were considered exposed if they were on treatment within a 30-day window before the index date. We estimated adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) using logistic regression. Results: Two thousand eight hundred and eighty-eight cases and 20 000 controls were included. No increased risk was observed with traditional NSAIDs as a group (OR = 1.03; 95% CI, 0.90-1.19), but results varied across individual agents and conditions of use. An increased risk was found with diclofenac (OR = 1.53; 95% CI, 1.19-1.97), in particular when used at high doses (OR = 1.62; 1.06-2.46), over long-term periods (> 365 days; OR = 2.39; 1.52-3.76) and in patients with a high background CV risk (OR = 1.78; 1.23-2.58), as well as with aceclofenac when used at high doses (OR = 1.67; 1.05-2.67), in long-term treatments (OR = 2.00; 1.14-3.53) and in patients with CV risk factors (OR = 2.33; 1.40-3.87). No association was found with ibuprofen (OR = 0.94; 0.76-1.17) or naproxen (OR = 0.68; 0.36-1.29). The concomitant use of aspirin did not show a significant effect modification. Paracetamol did not increase the risk overall (OR = 0.97; 0.85-1.10) or in patients at high CV risk (OR = 0.94; 0.78-1.14). Conclusions: Diclofenac and aceclofenac increase the risk of ischemic stroke while ibuprofen and naproxen do not. Dose, duration and baseline CV risk, but not aspirin use, appear to modulate the risk. Paracetamol does not increase the risk, even in patients with a high background CV risk. © 2015 International Society on Thrombosis and Haemostasis.


Martin-Merino E.,Spanish Center for Pharmacoepidemiological Research | Johansson S.,Astrazeneca | Johansson S.,Gothenburg University | Morris T.,Astrazeneca | Garcia Rodriguez L.A.,Spanish Center for Pharmacoepidemiological Research
Drug Safety | Year: 2011

Background: Androgen deprivation therapy (ADT) is used to delay tumour development and improve survival in patients with prostate cancer. However, several randomized controlled trials and observational studies have suggested that ADT may increase the risk of cardiovascular events. Objective: The aim of the study was to evaluate the risk of coronary heart disease (CHD) and heart failure (HF) in patients with prostate cancer receiving ADT in UK primary care, and to evaluate the risks associated with individual ADT and combination ADT. Methods: The UK General Practice Research Database was used to identify a cohort of patients with a first prostate cancer diagnosis during 1999-2005. These patients were followed up to assess the occurrence of acute myocardial infarction (AMI), death from CHD, incident HF and hospitalization due to acute decompensated HF. Nested case-control analyses were performed to assess the risk of these outcomes associated with anti-androgen therapy, as well as different types of ADT and combinations of ADT. Results: Current anti-androgen use was associated with a significant increase in the risk of hospitalization due to HF (odds ratio [OR] 2.15; 95% CI 1.08, 4.29), but not of incident HF, CHD or AMI. When assessed individually, there was no significant association of bicalutamide or cyproterone use with the risk of AMI or CHD. Current use of bicalutamide 50mg/day was associated with a significant increase in the risk of HF (OR 3.28; 95% CI 1.31, 8.18); however, this increased risk of HF was only found in patients taking bicalutamide 50 mg/day in combination with luteinizing hormone-releasing hormone (LHRH) receptor agonists. There were no cases of hospitalized HF in patients taking bicalutamide 50 mg/day as monotherapy and there was no significant association between current use of bicalutamide 150mg/day and the risk of hospitalized HF. Combination therapy with LHRH agonists and anti-androgens was associated with a significant increase in the risk of CHD (OR 4.35; 95%CI 1.94, 9.75), AMI (OR 3.57; 95%CI 1.44, 8.86), incident HF (OR 3.19; 95% CI 1.10, 9.27) and hospitalized HF (OR 3.39; 95% CI 1.07, 10.70) compared with non-use of these drugs.Conclusions: In men with prostate cancer, combination therapy with LHRH agonists and anti-androgens is associated with significant increases in the risk of CHD, AMI, incident HF and hospitalized HF. Individual therapies do not appear to increase the risk of these outcomes. © 2011 Adis Data Information BV. All rights reserved.


Garcia Rodriguez L.A.,Spanish Center for Pharmacoepidemiological Research | Lin K.J.,Harvard University | Hernandez-Diaz S.,Harvard University | Johansson S.,Gothenburg University
Circulation | Year: 2011

Background-This study evaluated the risk of upper gastrointestinal bleeding (UGIB) associated with use of low-dose acetylsalicylic acid (ASA) alone and in combination with other gastrotoxic medications. Methods and Results-The Health Improvement Network UK primary care database was used to identify individuals 40 to 84 years of age with a UGIB diagnosis in 2000 to 2007 (n=2049). An age-, sex-, and calendar year-matched control group (n=20 000) was identified from the same source population. The relative risk (RR) of UGIB associated with use of low-dose ASA (75 to 300 mg/d), clopidogrel, and other commonly coadministered medications was estimated by multivariate logistic regression. The risk of UGIB was increased in current users of low-dose ASA (RR, 1.80; 95% confidence interval [CI], 1.59 to 2.03) or clopidogrel (RR, 1.67; 95% CI, 1.24 to 2.24) compared with nonusers. Compared with low-dose ASA monotherapy, the risk of UGIB was significantly increased when low-dose ASA was coadministered with clopidogrel (RR, 2.08; 95% CI, 1.34 to 3.21), oral anticoagulants (RR, 2.00; 95% CI, 1.15 to 3.45), low-/medium-dose nonsteroidal antiinflammatory drugs (RR, 2.63; 95% CI, 1.93 to 3.60), high-dose nonsteroidal antiinflammatory drugs (RR, 2.66; 95% CI, 1.88 to 3.76), or high-dose oral corticosteroids (RR, 4.43; 95% CI, 2.10 to 9.34); this was not apparent with coadministration of statins (RR, 0.99; 95% CI, 0.81 to 1.21) or low-dose oral corticosteroids (RR, 1.01; 95% CI, 0.58 to 1.77). Conclusions-Use of low-dose ASA is associated with an almost 2-fold increase in the risk of UGIB compared with nonuse. This risk is increased further in individuals taking low-dose ASA along with clopidogrel, oral anticoagulants, nonsteroidal antiinflammatory drugs, or high-dose oral corticosteroids. © 2011 American Heart Association. All rights reserved.


Hernandez-Diaz S.,Harvard University | Martin-Merino E.,Spanish Center for Pharmacoepidemiological Research | Garcia Rodriguez L.A.,Spanish Center for Pharmacoepidemiological Research
Digestive Diseases and Sciences | Year: 2013

Background: Few studies have evaluated the prevention of upper gastrointestinal complications (UGIC; bleeding or perforation) in patients with uncomplicated peptic ulcer (PU). We assessed the effect of proton pump inhibitors (PPI) in a non-randomized setting. To maximize exchangeability of exposed and unexposed groups we restricted the study to patients with a new diagnosis of PU, i.e., a clear indication. To minimize selection bias we mimicked an intention to treat approach by assessing the effect of PPI prescription after PU diagnosis. Methods: Within a population of subjects aged 40-84 years from The Health Improvement Network database, 1997-2006, we identified 3,850 patients with incident PU. Among them, we confirmed 74 first UGIC episodes during a mean follow-up of 4 years. Exposure was prescription coverage during the month following PU diagnosis. We performed a nested case-control analysis and compared UGIC cases with 400 controls matched for age, sex, year and duration of follow-up. Relative risks (RR) and 95 % confidence intervals (CI) were estimated. Results: The overall incidence of UGIC was 4.6 cases/1,000 person-years; it was highest during the months after PU diagnosis, increased with age, and it was higher in men and subjects with Helicobacter pylori infection, anemia, and alcohol use at PU diagnosis. The RR for UGIC associated with PPI prescriptions during the month after PU diagnosis was 0.56 (95 % CI 0.31-1.0). The RR for NSAIDs with and without a PPI was 1.72 (0.68-4.45) and 3.27 (0.85-12.67), respectively. Conclusions: Findings suggest that prescription of PPIs after a PU diagnosis is associated with a reduced risk of UGIC. © 2013 Springer Science+Business Media New York.


Rodriguez G.,Spanish Center for Pharmacoepidemiological Research | Soriano L.C.,Spanish Center for Pharmacoepidemiological Research | Choi H.K.,Boston University
Annals of the Rheumatic Diseases | Year: 2010

Objective: Although hyperuricaemia and gout are associated with an increased future risk of diabetes, diabetes may reduce the future risk of gout through the uricosuric effect of glycosuria or the impaired inflammatory response. The present work evaluates the impact of diabetes on the future risk of developing gout. Methods: A case-control study nested in a UK general practice database (the health improvement network) was conducted by identifying all incident cases of gout (N=24 768) and randomly sampling 50 000 controls who were 20-89 years between 2000 and 2007. The independent effect of type 1 and type 2 diabetes on the development of incident gout was examined. Results: After adjusting for age, sex, body mass index, general practitioner visits, smoking, alcohol intake, ischaemic heart disease and presence of cardiovascular risk factors, the RR for incident gout among patients with diabetes, as compared with individuals with no diabetes was 0.67 (95% CI 0.63 to 0.71). The multivariate RRs with the duration of diabetes of 0-3, 4-9 and ≥10 years were 0.81 (95% CI 0.74 to 0.90), 0.67 (95% CI 0.61 to 0.73) and 0.52 (95% CI 0.46 to 0.58), respectively. The inverse association was stronger with type 1 diabetes than with type 2 diabetes (multivariate RR, 0.33 vs 0.69) and stronger among men than women (p value for interaction <0.001). Conclusions: Individuals with diabetes are at a lower future risk of gout independent of other risk factors. These data provide support for a substantial role of the pathophysiology associated with diabetes against the risk of developing gout.


Choi H.K.,Boston University | Soriano L.C.,Spanish Center for Pharmacoepidemiological Research | Zhang Y.,Boston University | Garcia Rodriguez L.A.,Spanish Center for Pharmacoepidemiological Research
BMJ (Online) | Year: 2012

Objective: To determine the independent associations of antihypertensive drugs with the risk of incident gout among people with hypertension. Design: Nested case-control study. Setting: UK general practice database, 2000-7. Participants: All incident cases of gout (n=24 768) among adults aged 20-79 and a random sample of 50 000 matched controls. Main outcome measure: Relative risk of incident gout associated with use of antihypertensive drugs. Results: After adjusting for age, sex, body mass index, visits to the general practitioner, alcohol intake, and pertinent drugs and comorbidities, the multivariate relative risks of incident gout associated with current use of antihypertensive drugs among those with hypertension (n=29 138) were 0.87 (95% confidence interval 0.82 to 0.93) for calcium channel blockers, 0.81 (0.70 to 0.94) for losartan, 2.36 (2.21 to 2.52) for diuretics, 1.48 (1.40 to 1.57) for β blockers, 1.24 (1.17 to 1.32) for angiotensin converting enzyme inhibitors, and 1.29 (1.16 to 1.43) for non-losartan angiotensin II receptor blockers. Similar results were obtained among those without hypertension. The multivariate relative risks for the duration of use of calcium channel blockers among those with hypertension were 1.02 for less than one year, 0.88 for 1-1.9 years, and 0.75 for two or more years and for use of losartan they were 0.98, 0.87, and 0.71, respectively (both P<0.05 for trend). Conclusions: Compatible with their urate lowering properties, calcium channel blockers and losartan are associated with a lower risk of incident gout among people with hypertension. By contrast, diuretics, β blockers, angiotensin converting enzyme inhibitors, and non-losartan angiotensin II receptor blockers are associated with an increased risk of gout.

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