Validation of cardiovascular outcomes and risk factors in the Clinical Practice Research Datalink in the United Kingdom.

PURPOSE: Strategies to identify and validate acute myocardial infarction (AMI) and stroke in primary-care electronic records may impact effect measures, but to an unknown extent. Additionally, the validity of cardiovascular risk factors that could act as confounders in studies on those endpoints has not been thoroughly assessed in the United Kingdom Clinical Practice Research Datalink's (CPRD's) GOLD database. We explored the validity of algorithms to identify cardiovascular outcomes and risk factors and evaluated different outcome-identification strategies using these algorithms for estimation of adjusted incidence rate ratios (IRRs). METHODS: First, we identified AMI, stroke, smoking, obesity, and menopausal status in a cohort treated for overactive bladder by applying computerized algorithms to primary care medical records (2004-2012). We validated these cardiovascular outcomes and risk factors with physician questionnaires (gold standard for this analysis). Second, we estimated IRRs for AMI and stroke using algorithm-identified and questionnaire-confirmed cases, comparing these with IRRs from cases identified through linkage with hospitalization/mortality data (best estimate). RESULTS: For AMI, the algorithm's positive predictive value (PPV) was >90%. Initial algorithms for stroke performed less well because of inclusion of codes for prevalent stroke; algorithm refinement increased PPV to 80% but decreased sensitivity by 20%. Algorithms for smoking and obesity were considered valid. IRRs based on questionnaire-confirmed cases only were closer to IRRs estimated from hospitalization/mortality data than IRRs from algorithm-identified cases. CONCLUSIONS: AMI, stroke, smoking, obesity, and postmenopausal status can be accurately identified in CPRD. Physician questionnaire-validated AMI and stroke cases yield IRRs closest to the best estimate.

Comparison of cardiovascular events among treatments for overactive bladder: a Danish nationwide cohort study.

PURPOSE: The purpose of this study is to explore the cardiovascular safety of antimuscarinic drugs to treat overactive bladder (OAB) in Denmark. METHODS: This was a cohort study using data recorded in Danish registries from patients newly exposed to darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, or trospium in 2004-2012. We estimated crude and standardized incidence rates (IRs) for acute myocardial infarction (AMI); stroke; cardiovascular mortality; major adverse cardiac events (MACE, a combined endpoint of the previous three outcomes); and all-cause death for the individual and combined drugs. We also estimated crude, standardized, and propensity score-stratified incidence rate ratios (IRRs) comparing individual antimuscarinic drugs to tolterodine as the reference. RESULTS: Among 72,917 new users of OAB drugs (mean age, 66 years; 60% women), the standardized IR (95% confidence interval) per 1000 person-years for current use of any OAB drug was 2.7 (2.5-2.9) for AMI, 1.3 (1.2-1.5) for stroke, 7.8 (7.5-8.1) for MACE, 4.8 (4.5-5.0) for cardiovascular mortality, and 15.2 (14.8-15.6) for all-cause mortality. Propensity score-stratified IRRs for current use (reference, tolterodine) were close to the null for all drugs and endpoints. CONCLUSIONS: We did not identify differences in the risk of cardiovascular events or mortality among users of individual antimuscarinic OAB drugs.

Methodological challenges when evaluating potential off-label prescribing of drugs using electronic health care databases: A case study of dabigatran etexilate in Europe.

PURPOSE: To report and discuss estimated prevalence of potential off-label use and associated methodological challenges using a case study of dabigatran. METHODS: Observational, cross-sectional study using 3 databases with different types of clinical information available: Cegedim Strategic Data Longitudinal Patient Database (CSD-LPD), France (cardiologist panel, n = 1706; general practitioner panel, n = 2813; primary care data); National Health Databases, Denmark (n = 28 619; hospital episodes and dispensed ambulatory medications); and Clinical Practice Research Datalink (CPRD), UK (linkable to Hospital Episode Statistics [HES], n = 2150; not linkable, n = 1285; primary care data plus hospital data for HES-linkable patients). STUDY PERIOD: August 2011 to August 2015. Two definitions were used to estimate potential off-label use: a broad definition of on-label prescribing using codes for disease indication (eg, atrial fibrillation [AF]), and a restrictive definition excluding patients with conditions for which dabigatran is not indicated (eg, valvular AF). RESULTS: Prevalence estimates under the broad definition ranged from 5.7% (CPRD-HES) to 34.0% (CSD-LPD) and, under the restrictive definition, from 17.4% (CPRD-HES) to 44.1% (CSD-LPD). For the majority of potential off-label users, no diagnosis potentially related to anticoagulant use was identified. Key methodological challenges were the limited availability of detailed clinical information, likely leading to overestimation of off-label use, and differences in the information available, which may explain the disparate prevalence estimates across data sources. CONCLUSIONS: Estimates of potential off-label use should be interpreted cautiously due to limitations in available information. In this context, CPRD HES-linkable estimates are likely to be the most accurate.

Characterization of new users of cilostazol in the UK, Spain, Sweden, and Germany.

PURPOSE: To describe the characteristics of new users of cilostazol in Europe with the aim to support the evaluation of its benefit/risk as used in regular clinical practice before the implementation of labeling changes recommended by the European Medicines Agency. METHODS: New users of cilostazol were identified in populations enrolled in five European health automated databases in the UK (The Health Improvement Network [THIN]), Spain (EpiChron cohort and Information System for the Improvement of Research in Primary Care [SIDIAP]), Sweden (National Registers), and Germany (German Pharmacoepidemiological Research Database [GePaRD]) between 2002 and 2012. New users were characterized according to the prevalence of cardiovascular disease and other comorbidities, concurrent use of interacting medications, new contraindications, duration of use, and potential off-label prescribing. RESULTS: We identified 22 593 new users of cilostazol. The median age was between 68.0 (THIN) and 73.7 (Sweden) years. More than 78% of users had concomitant cardiovascular disease, and between 78.8% (GePaRD) and 91.6% (THIN) were treated with interacting medications. Prevalence of new cardiovascular contraindications ranged from 1.5% (THIN) to 11.6% (GePaRD), and concurrent use of two or more antiplatelet drugs ranged from 6.3% (SIDIAP) to 13.5% (EpiChron cohort). Between 39.4% (Sweden) and 52.9% (THIN) of users discontinued cilostazol in the first 3 months. Between 41.0% (SIDIAP) and 93.4% (THIN) were considered to have received cilostazol according to the European Medicines Agency labeling. CONCLUSIONS: In this collaborative European study, most cilostazol users were elderly patients with a high prevalence of cardiovascular diseases and other comorbidity and concurrent use of interacting drugs, indicating that this is a vulnerable population at high risk of complications, especially cardiovascular events. © 2017 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

Cardiovascular risk associated with the use of glitazones, metformin and sufonylureas: meta-analysis of published observational studies.

BACKGROUND: The results of observational studies evaluating and comparing the cardiovascular safety of glitazones, metformin and sufonylureas are inconsistent.To conduct and evaluate heterogeneity in a meta-analysis of observational studies on the risk of acute myocardial infarction (AMI) or stroke in patients with type 2 diabetes using non-insulin blood glucose-lowering drugs (NIBGLD). METHODS: We systematically identified and reviewed studies evaluating NIBGLD in patients with type 2 diabetes indexed in Medline, Embase, or the Cochrane Library that met prespecified criteria. The quality of included studies was assessed with the RTI item bank. Results were combined using fixed- and random-effects models, and the Higgins I(2) statistic was used to evaluate heterogeneity. Sensitivity analyses by study quality were conducted. RESULTS: The summary relative risk (sRR) (95% CI) of AMI for rosiglitazone versus pioglitazone was 1.13 (1.04-1.24) [I(2) = 55%]. In the sensitivity analysis, heterogeneity was reduced [I(2) = 16%]. The sRR (95% CI) of stroke for rosiglitazone versus pioglitazone was 1.18 (1.02-1.36) [I(2) = 42%]. There was strong evidence of heterogeneity related to study quality in the comparisons of rosiglitazone versus metformin and rosiglitazone versus sulfonylureas (I (2) ≥ 70%). The sRR (95% CI) of AMI for sulfonylurea versus metformin was 1.24 (1.14-1.34) [I(2) = 41%] and for pioglitazone versus metformin was 1.02 (0.75-1.38) [I(2) = 17%]. Sensitivity analyses decreased heterogeneity in most comparisons. CONCLUSION/INTERPRETATION: Sulfonylureas increased the risk of AMI by 24% compared with metformin; an imprecise point estimate indicated no difference in risk of AMI when comparing pioglitazone with metformin. The presence of heterogeneity precluded any conclusions on the other comparisons. The quality assessment was valuable in identifying methodological problems in the individual studies and for analysing potential sources of heterogeneity.

The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are at high risk of heart failure. A summary of the effects of blood glucose-lowering drugs other than glitazones on the risk of heart failure in routine clinical practice is lacking. The objective of this study was to conduct a systematic review and meta-analysis of observational studies on the risk of heart failure when using blood glucose-lowering drugs. METHODS: We systematically identified and reviewed cohort and case-control studies in which the main exposure of interest was noninsulin blood glucose-lowering medications in patients with T2DM. We searched Medline, Embase, and the Cochrane Library to identify publications meeting prespecified eligibility criteria. The quality of included studies was assessed with the Newcastle-Ottawa Scale and the RTI item bank. Results were combined using fixed and random-effects models when at least 3 independent data points were available for a drug-drug comparison. RESULTS: The summary relative risk of heart failure in rosiglitazone users versus pioglitazone users (95% CI) was 1.16 (1.05-1.28) (5 cohort studies). Heterogeneity was present (I2 = 66%). For new users (n = 4) the summary relative risk was 1.21 (1.14-1.30) and the heterogeneity was reduced (I2 = 31%);. The summary relative risk for rosiglitazone versus metformin was 1.36 (95% CI, 1.17-1.59) (n = 3). The summary relative risk (95% CI) of heart failure in sulfonylureas users versus metformin users was 1.17 (95% CI, 1.06-1.29) (5 cohort studies; I2 = 24%) and 1.22 (1.02-1.46) when restricted to new users (2 studies).Information on other comparisons was very scarce. Information on dose and duration of treatment effects was lacking for most comparisons. Few studies accounted for disease severity; therefore, confounding by indication might be present in the majority of the within-study comparisons of this meta-analysis. CONCLUSIONS: Use of glitazones and sulfonylureas was associated with an increased risk of heart failure compared with metformin use. However, indication bias cannot be ruled out. Ongoing large multidatabase studies will help to evaluate the risk of heart failure in treated patients with diabetes, including those using newer blood glucose-lowering therapies.

Myocardial infarction and individual nonsteroidal anti-inflammatory drugs meta-analysis of observational studies.

OBJECTIVE: To conduct a systematic review of observational studies on the risk of acute myocardial infarction (AMI) with use of individual nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: A search of Medline (PubMed) for observational studies published from 1990 to 2011 identified 3829 articles; 31 reported relative risk (RR) of AMI with use of individual NSAIDs versus nonuse of NSAIDs. Information abstracted in a standardized form from 25 publications was used for the meta-analysis on 18 independent study populations. RESULTS: Random-effects RR (95% confidence interval (CI)) was lowest for naproxen 1.06 (0.94­1.20), followed by celecoxib 1.12 (1.00­1.24), ibuprofen 1.14 (0.98­1.31), meloxicam 1.25 (1.04­1.49), rofecoxib 1.34 (1.22­1.48), diclofenac 1.38 (1.26­1.52), indometacin 1.40 (1.21­1.62), etodolac 1.55 (1.16­2.06), and etoricoxib 1.97 (1.35­2.89). Heterogeneity between studies was present. For new users, RRs (95% CIs) were for naproxen, 0.85 (0.73­1.00); ibuprofen, 1.20 (0.97­1.48); celecoxib, 1.23 (1.00­1.52); diclofenac, 1.41 (1.08­1.86); and rofecoxib, 1.43 (1.21­1.66).Except for naproxen, higher risk was generally associated with higher doses, as defined in each study, overall and in patients with prior coronary heart disease. Low and high doses of diclofenac and rofecoxib were associated with high risk of AMI, with dose­response relationship for rofecoxib. In patients with prior coronary heart disease, except for naproxen, duration of use ≤3 months was associated with an increased risk of AMI. CONCLUSIONS: Most frequently NSAIDs used in clinical practice, except naproxen, are associated with an increased risk of AMI at high doses or in persons with diagnosed coronary heart disease. For diclofenac and rofecoxib, the risk was increased at low and high doses.

Stroke risk and NSAIDs: a systematic review of observational studies.

AIMS: To perform a quantitative systematic review of observational studies on the risk of stroke associated with the use of individual NSAIDs. METHODS AND RESULTS: Searches were conducted using the Medline database within PubMed (1990-2008). Observational cohort or case-control studies were eligible if reported on the risk of cardiovascular events associated with individual NSAIDs versus the nonuse of NSAIDs. We found 3193 articles, in which 75 were eligible for review and abstraction. Of the 75 articles, 6 reported relative risk (RR) of stroke. Data were abstracted into a database using a standardized entry form. Two authors assessed study quality, and discrepancies were resolved by consensus. The pooled RR of all subtypes of incident stroke was increased with the current use of rofecoxib (RR = 1.64, 95% CI = 1.15-2.33) and diclofenac (RR = 1.27, 95% CI = 1.08-1.48). The pooled estimates for naproxen, ibuprofen, and celecoxib were close to unity. The risk of ischemic stroke was also increased with rofecoxib (RR = 1.82, 95% CI = 1.09-3.04) and diclofenac (RR = 1.20, 95% CI = 0.99-1.45). Data were inadequate to estimate the pooled RR by dose and duration, for other individual NSAIDs or nonischemic stroke subtypes. CONCLUSION: This meta-analysis supports an increased risk of ischemic stroke with the current use of rofecoxib and diclofenac. Additional studies are required to evaluate most individual NSAIDS, the effect of dose and duration, and the subtypes of stroke.

Risk of serious ventricular arrhythmia and sudden cardiac death in a cohort of users of domperidone: a nested case-control study.

PURPOSE: Limited information from spontaneous reports and results of two case-control studies raised concern about the cardiotoxicity of oral domperidone therapy. This case-control study nested in a retrospective cohort evaluated the combined risk of serious ventricular arrhythmia (SVA) and sudden cardiac death (SCD) in users of domperidone compared with users of proton pump inhibitors (PPIs), or non-users of these medications. METHODS: A cohort of users of domperidone or a PPI from 1990 to 2005 was identified from existing electronic databases of Saskatchewan Health. Possible cases of SVA/SCD were identified using hospital discharge and vital statistics codes. SVA cases were validated by cardiologist review of abstracted hospital medical charts. Up to four controls were matched to each case by index date, year of birth, sex, and diabetes status. The odds ratio (OR) of current domperidone exposure relative to non-use or to current PPI exposure was estimated and adjusted for possible confounding variables using conditional logistic regression. RESULTS: From 83 212 individuals in the exposure cohort we identified 1608 cases, 49 SVA and 1559 SCD (mean age 79.4 years, females 52.9%, diabetes 22.3%) and 6428 matched controls. The adjusted OR for SVA/SCD with current domperidone use compared with non-use was (1.59, 95%CI: 1.28-1.98), or compared with current PPI use was (1.44, 95%CI: 1.12-1.86). In stratified analyses adjusted ORs were numerically higher in males, older subjects, and non-diabetics. CONCLUSIONS: The increased risk of SVA/SCD for current domperidone users remained after adjustment for multiple covariates. The risk may vary among subgroups of exposed individuals.

The use of selective cyclooxygenase-2 inhibitors and the risk of acute myocardial infarction in Saskatchewan, Canada.

BACKGROUND: Meta-analyses of observational studies show variability in the risk of acute myocardial infarction (AMI) among non-steroidal anti-inflammatory drugs (NSAIDs), with an increase in risk for rofecoxib and diclofenac, and no increase in risk for celecoxib, naproxen, or ibuprofen. METHODS AND RESULTS: We identified a cohort of 364 658 individuals aged 40-84 years who were enrolled in Saskatchewan Health, Canada, from 15 November 1999 to 31 December 2001. A nested case-control analysis compared 3252 incident cases of hospitalized AMI and out-of-hospital CHD deaths with 20 002 controls randomly sampled from the cohort. The incidence of AMI/CHD was 5.1 per 1000 person-years (95%CI: 5.0-5.3). The adjusted ORs (95%CI) of AMI/CHD in current users of individual NSAIDs compared with non-use were: celecoxib (1.11; 0.84-1.47), rofecoxib (1.32; 0.91-1.91), diclofenac (1.02; 0.75-1.38), naproxen (1.57; 0.98-2.52), ibuprofen (1.59; 0.88-2.89), and indomethacin (1.34; 0.81-2.19). Long-term use of rofecoxib was compatible with an increased risk (OR = 1.46; 0.97-2.22) while estimates of other individual NSAIDs were close to unity. Overall NSAID use was associated with a 30% increased risk of nonfatal AMI but was absent for fatal AMI/CHD. CONCLUSIONS: This study showed a modest increased risk of AMI/CHD with various traditional NSAIDs and COX-2 inhibitors. Confidence intervals of estimated ORs included the null value for most comparisons. The study confirmed that the differentiation between traditional NSAIDs and COX-2 inhibitors is not a reliable tool for predicting cardiovascular risk associated with NSAIDs.

Positive predictive value of ICD-9 codes 410 and 411 in the identification of cases of acute coronary syndromes in the Saskatchewan Hospital automated database.

BACKGROUND: Case definitions are essential to epidemiological research. OBJECTIVES: To evaluate ICD-9 codes 410 and 411 to identify cases of acute coronary syndromes (ACS), and the clinical information availability in the administrative and hospital discharge records of Saskatchewan, Canada. METHODS: In the context of a safety cohort study, we identified hospitalisations with primary discharge codes 410 (2260) and 411 (799). We selected all records with code 411, and a random sample (200) with code 410. Based on information obtained by trained abstractors from hospital records, events were classified by two cardiologists as definite or possible according to adapted AHA/ESC criteria. The validity of 410 and 411 codes was assessed by calculating the positive predictive value (PPV). Completeness of the recorded information on risk factors and use of aspirin was explored. RESULTS: The PPVs of the codes 410 and 411 for ACS were 0.96 (95%CI: 0. 92-0.98) and 0.86 (95%CI: 0.83-0.88), respectively. The PPV of 410 for acute myocardial infarction (AMI) was 0.95 (95%CI: 0.91-0.98). The PPV of 411 was 0.73 (95%CI: 0.70-0.77) for primary unstable angina (UA) and 0.09 (95%CI: 0.07-0.11) for AMI. Hospital charts review revealed key information for clinical variables, smoking, obesity and use of aspirin at admission. CONCLUSIONS: ICD-9 410 code has high PPV for AMI cases, likewise 411 for UA cases. Case validation remains important in epidemiological studies with administrative health databases. Given the pathophysiology of ACS, both AMI and UA might be used as study end points. In addition to code 410, we recommend the use of 411 plus validation.

Variation in Cardiovascular Risk Related to Individual Antimuscarinic Drugs Used to Treat Overactive Bladder: A UK Cohort Study.

BACKGROUND: Blocking muscarinic receptors could have an effect on cardiac function, especially among elderly patients with overactive bladder (OAB). STUDY OBJECTIVE: To investigate the risk of cardiovascular (CV) events in users of antimuscarinic drugs to treat OAB. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of new users of darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, or trospium, 18 years or older, in the United Kingdom's Clinical Practice Research Datalink (CPRD), 2004-2012. OUTCOME MEASUREMENTS AND MAIN RESULTS: Using tolterodine as the reference, we estimated propensity-score-stratified incidence rate ratios (IRRs) for acute myocardial infarction, stroke, CV mortality, major adverse cardiac events (MACE, a combined end point of the previous three), and all-cause death for individual antimuscarinic drugs. The study cohort included 119,912 new users of OAB drugs. The mean age at cohort entry was 62 years, 70% were female, and the mean follow-up was 3.3 years. The adjusted IRR for MACE and current use of oxybutynin compared with current use of tolterodine was 1.14 (95% confidence interval [CI] 1.01-1.30). In contrast, the IRR was 0.65 (CI 0.56-0.76) for current use of solifenacin compared with tolterodine. In this study, performed with health care data, the distribution of risk factors was relatively similar across users of different OAB drugs and, although our analyses controlled for a range of measured potential confounders, residual confounding cannot be ruled out. CONCLUSIONS: In an observational comparative study of users of medications to treat OAB conducted in routine clinical practice, the risk for CV side effects was increased in users of oxybutynin and decreased in users of solifenacin compared with users of tolterodine.

Risk of acute myocardial infarction during use of individual NSAIDs: A nested case-control study from the SOS project.

BACKGROUND: Use of selective COX-2 non-steroidal anti-inflammatory drugs (NSAIDs) (coxibs) has been associated with an increased risk of acute myocardial infarction (AMI). However, the risk of AMI has only been studied for very few NSAIDs that are frequently used. OBJECTIVES: To estimate the risk of AMI for individual NSAIDs. METHODS: A nested case-control study was performed from a cohort of new NSAID users ≥18 years (1999-2011) matching cases to a maximum of 100 controls on database, sex, age, and calendar time. Data were retrieved from six healthcare databases. Adjusted odds ratios (ORs) of current use of individual NSAIDs compared to past use were estimated per database. Pooling was done by two-stage pooling using a random effects model (ORmeta) and by one-stage pooling (ORpool). RESULTS: Among 8.5 million new NSAID users, 79,553 AMI cases were identified. The risk was elevated for current use of ketorolac (ORmeta 2.06;95%CI 1.83-2.32, ORpool 1.80; 1.49-2.18) followed, in descending order of point estimate, by indometacin, etoricoxib, rofecoxib, diclofenac, fixed combination of diclofenac with misoprostol, piroxicam, ibuprofen, naproxen, celecoxib, meloxicam, nimesulide and ketoprofen (ORmeta 1.12; 1.03-1.22, ORpool 1.00;0.86-1.16). Higher doses showed higher risk estimates than lower doses. CONCLUSIONS: The relative risk estimates of AMI differed slightly between 28 individual NSAIDs. The relative risk was highest for ketorolac and was correlated with COX-2 potency, but not restricted to coxibs.

Risk of ischemic stroke and the use of individual non-steroidal anti-inflammatory drugs: A multi-country European database study within the SOS Project.

BACKGROUND AND PURPOSE: A multi-country European study using data from six healthcare databases from four countries was performed to evaluate in a large study population (>32 million) the risk of ischemic stroke (IS) associated with individual NSAIDs and to assess the impact of risk factors of IS and co-medication. METHODS: Case-control study nested in a cohort of new NSAID users. For each case, up to 100 sex- and age-matched controls were selected and confounder-adjusted odds ratios for current use of individual NSAIDs compared to past use calculated. RESULTS: 49,170 cases of IS were observed among 4,593,778 new NSAID users. Use of coxibs (odds ratio 1.08, 95%-confidence interval 1.02-1.15) and use of traditional NSAIDs (1.16, 1.12-1.19) were associated with an increased risk of IS. Among 32 individual NSAIDs evaluated, the highest significant risk of IS was observed for ketorolac (1.46, 1.19-1.78), but significantly increased risks (in decreasing order) were also found for diclofenac, indomethacin, rofecoxib, ibuprofen, nimesulide, diclofenac with misoprostol, and piroxicam. IS risk associated with NSAID use was generally higher in persons of younger age, males, and those with a prior history of IS. CONCLUSIONS: Risk of IS differs between individual NSAIDs and appears to be higher in patients with a prior history of IS or transient ischemic attack (TIA), in younger or male patients. Co-medication with aspirin, other antiplatelets or anticoagulants might mitigate this risk. The small to moderate observed risk increase (by 13-46%) associated with NSAIDs use represents a public health concern due to widespread NSAID usage.

Use of oral corticosteroids and the risk of acute myocardial infarction.

INTRODUCTION: A few epidemiological studies suggested an increased coronary heart disease (CHD) risk with high doses of oral corticosteroids. METHODS: We performed a cohort study with nested case-control analysis to estimate the risk of acute myocardial infarction (AMI) associated with the use of oral corticosteroids by dose and duration. We followed-up 404,183 persons, 50-84 years old, without cancer from the general UK population. After validation of a random sample (confirmation rate of 96%), we included 4795 hospitalised cases of AMI or CHD deaths. We randomly sampled 20,000 controls, frequency matched by sex, age and calendar year. Relative risks were estimated using unconditional logistic regression. RESULTS: The adjusted OR for AMI in current users of oral corticosteroids compared to non-users was 1.42 (95% CI: 1.17-1.72). The risk during the first 30 days of use (OR=2.24; 95% CI: 1.56-3.20) was greater than with longer duration (OR=1.22; 95% CI 0.98-1.52). The risk was more pronounced (OR=2.15; 95% CI 1.45-3.14) among users of prednisolone equivalent doses >10mg/day. The dose effect was observed both among patients with and without CHD or COPD/asthma. CONCLUSION: These results suggest a small increased risk of AMI with oral corticosteroid use with a greater risk observed among users of high corticosteroid dose.

Non-steroidal antiinflammatory drugs and the risk of acute myocardial infarction.

Whether non-aspirin non-steroidal antiinflammatory drugs (NSAIDs) affect the risk of myocardial infarction is unclear. Also, it is unknown whether the effect varies by individual NSAIDs. To summarize the evidence from published observational studies on the risk of myocardial infarction associated with both traditional NSAIDs (tNSAIDs) and selective inhibitors of cyclooxygenase-2 (Coxibs), the authors conducted a systematic review of cohort and case-control studies on NSAIDs and myocardial infarction published between 2000 and 2005. Sixteen original studies were selected according to predefined criteria. Two researchers independently extracted the data on individual study characteristics and results. The authors calculated pooled relative risk (RR) estimates of myocardial infarction for specific NSAIDs compared with no NSAID use, tested the heterogeneity of effects, and evaluated potential reasons for heterogeneity. The pooled RR of myocardial infarction was 0.98 (95% confidence interval (CI): 0.92-1.05) for naproxen, 1.07 (95% CI: 1.02-1.12) for ibuprofen, 1.44 (95% CI: 1.32-1.56) for diclofenac, 0.96 (95% CI: 0.90-1.02) for celecoxib, and 1.26 (95% CI: 1.17-1.36) for rofecoxib (all doses). The pooled RR for rofecoxib at doses >25 mg/day was 1.78 (95% CI: 1.36-2.34), and 1.18 (95% CI: 1.07-1.31) for doses < or =25 mg/day. The RR associated with naproxen was 0.83 (95% CI: 0.72-0.90) among non-users of low-dose aspirin. The RR associated with rofecoxib (all doses) was 1.39 (95% CI: 1.25-1.54) among subjects without a history of myocardial infarction. The risk of myocardial infarction varies with individual NSAIDs. An increased risk was observed for diclofenac and rofecoxib, the latter one with a clear dose-response trend. There was a suggestion of a small increased risk with ibuprofen. Also, data suggest a small reduced risk for naproxen present only in non-users of aspirin, mainly people free of clinically apparent vascular disease.

Improving the Identification of Out-of-Hospital Sudden Cardiac Deaths in a General Practice Research Database.

BACKGROUND: The ascertainment of sudden cardiac death (SCD) in electronic health databases is challenging. OBJECTIVES: Our objective was to evaluate the applicability of the validated computer definition of SCD developed by Chung et al. in a retrospective study of SCD and domperidone exposure in the Clinical Practice Research Datalink (CPRD). METHODS: We assessed out-of-hospital SCD by applying the validated computer definition and linking data with Hospital Episode Statistics and death certificates. We developed a separate algorithm to identify end-of-life care in noninstitutionalized patients and excluded associated deaths from the analysis to address their misclassification as SCD. RESULTS: Of the 681,104 patients in the study cohort, 3444 were initially classified as out-of-hospital SCD. Next, 163 deaths were identified as expected deaths by our algorithm for end-of-life home care. After review of patient profiles, 162 were classified as expected deaths because of evidence that the patient received palliative or end-of-life care, but one was a false negative. The exclusion of such cases appreciably changed the odds ratio for current exposure to domperidone compared with non-use of study medications from 2.09 (95 % confidence interval [CI] 1.16-3.74) to 1.71 (95 % CI 0.92-3.18). A similar effect on the odds ratio was observed for current exposure to metoclopramide but not to proton pump inhibitors. CONCLUSIONS: Our algorithm to identify end-of-life care at home in the CPRD performed well, with only one false negative. The exclusion of misclassified cases of SCD reduced the magnitude of the odds ratios for SCD associated with domperidone and metoclopramide exposure by controlling protopathic bias.

Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study.

OBJECTIVES: To investigate the cardiovascular safety of non-steroidal anti-inflammatory drugs (NSAIDs) and estimate the risk of hospital admission for heart failure with use of individual NSAIDs. DESIGN: Nested case-control study. SETTING: Five population based healthcare databases from four European countries (the Netherlands, Italy, Germany, and the United Kingdom). PARTICIPANTS: Adult individuals (age ≥18 years) who started NSAID treatment in 2000-10. Overall, 92 163 hospital admissions for heart failure were identified and matched with 8 246 403 controls (matched via risk set sampling according to age, sex, year of cohort entry). MAIN OUTCOME MEASURE: Association between risk of hospital admission for heart failure and use of 27 individual NSAIDs, including 23 traditional NSAIDs and four selective COX 2 inhibitors. Associations were assessed by multivariable conditional logistic regression models. The dose-response relation between NSAID use and heart failure risk was also assessed. RESULTS: Current use of any NSAID (use in preceding 14 days) was found to be associated with a 19% increase of risk of hospital admission for heart failure (adjusted odds ratio 1.19; 95% confidence interval 1.17 to 1.22), compared with past use of any NSAIDs (use >183 days in the past). Risk of admission for heart failure increased for seven traditional NSAIDs (diclofenac, ibuprofen, indomethacin, ketorolac, naproxen, nimesulide, and piroxicam) and two COX 2 inhibitors (etoricoxib and rofecoxib). Odds ratios ranged from 1.16 (95% confidence interval 1.07 to 1.27) for naproxen to 1.83 (1.66 to 2.02) for ketorolac. Risk of heart failure doubled for diclofenac, etoricoxib, indomethacin, piroxicam, and rofecoxib used at very high doses (≥2 defined daily dose equivalents), although some confidence intervals were wide. Even medium doses (0.9-1.2 defined daily dose equivalents) of indomethacin and etoricoxib were associated with increased risk. There was no evidence that celecoxib increased the risk of admission for heart failure at commonly used doses. CONCLUSIONS: The risk of hospital admission for heart failure associated with current use of NSAIDs appears to vary between individual NSAIDs, and this effect is dose dependent. This risk is associated with the use of a large number of individual NSAIDs reported by this study, which could help to inform both clinicians and health regulators.

Nonsteroidal antiinflammatory drugs and the risk of myocardial infarction in the general population.

BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) are reversible inhibitors of cyclooxygenase (COX)-1 and COX-2. Whether transient and incomplete COX-1 inhibition with NSAIDs other than aspirin will translate into clinical cardioprotection is unclear. Some reports suggest that concurrent aspirin and ibuprofen might be associated with lower cardioprotection than aspirin alone because of a pharmacodynamic interaction. METHODS AND RESULTS: We conducted a cohort study with a nested case-control analysis. Overall, 4975 cases of acute myocardial infarction (MI) and death from coronary heart disease (CHD) were identified (January 1997 to December 2000) in the UK. A total of 20,000 controls were randomly sampled, and frequency was matched to cases by age, sex, and calendar year. The incidence rate was 5.0 per 1000 person-years. The multivariate-adjusted OR for current NSAID use compared with nonuse was 1.07 (95% CI, 0.95 to 1.20). Treatment duration or daily dose did not change the results. The effect was similar among patients free of CHD history (1.04; 95% CI, 0.90 to 1.20) and patients with previous history (1.12; 95% CI, 0.91 to 1.38). Estimates for individual NSAIDs were all comparable, with no major effect on the risk of acute MI. Naproxen was associated with an OR of 0.89 (95% CI, 0.64 to 1.24). The OR of aspirin and concurrent NSAIDs use was 1.10 (95% CI, 0.89 to 1.37) compared with aspirin alone. We observed the same result when analyzing ibuprofen and aspirin taken concomitantly. CONCLUSIONS: This study could not demonstrate any detectable risk reduction of NSAIDs on the occurrence of MI. Our results do not support the existence of a clinically meaningful interaction between aspirin and NSAIDs, including ibuprofen.