Validity of ICD-9 and ICD-10 codes used to identify acute liver injury: A study in three European data sources.

PURPOSE: Validating cases of acute liver injury (ALI) in health care data sources is challenging. Previous validation studies reported low positive predictive values (PPVs). METHODS: Case validation was undertaken in a study conducted from 2009 to 2014 assessing the risk of ALI in antidepressants users in databases in Spain (EpiChron and SIDIAP) and the Danish National Health Registers. Three ALI definitions were evaluated: primary (specific hospital discharge codes), secondary (specific and nonspecific hospital discharge codes), and tertiary (specific and nonspecific hospital and outpatient codes). The validation included review of patient profiles (EpiChron and SIDIAP) and of clinical data from medical records (EpiChron and Denmark). ALI cases were confirmed when liver enzyme values met a definition by an international working group. RESULTS: Overall PPVs (95% CIs) for the study ALI definitions were, for the primary ALI definition, 84% (60%-97%) (EpiChron), 60% (26%-88%) (SIDIAP), and 74% (60%-85%) (Denmark); for the secondary ALI definition, 65% (45%-81%) (EpiChron), 40% (19%-64%) (SIDIAP), and 70% (64%-77%) (Denmark); and for the tertiary ALI definition, 25% (18%-34%) (EpiChron), 8% (7%-9%) (SIDIAP), and 47% (42%-52%) (Denmark). The overall PPVs were higher for specific than for nonspecific codes and for hospital discharge than for outpatient codes. The nonspecific code "unspecified jaundice" had high PPVs in Denmark. CONCLUSIONS: PPVs obtained apply to patients using antidepressants without preexisting liver disease or ALI risk factors. To maximize validity, studies on ALI should prioritize hospital specific discharge codes and should include hospital codes for unspecified jaundice. Case validation is required when ALI outpatient cases are considered.

Use of aclidinium did not increase the risk of death in a noninterventional cohort study in the Clinical Practice Research Datalink (CPRD), United Kingdom.

BACKGROUND: Aclidinium bromide is an inhaled long-acting muscarinic antagonist (LAMA). Although the initial potential increased cardiovascular and mortality risk among users of tiotropium has been ruled out by several observational studies, and clinical trials, there are still concerns related to the use of newer LAMA medications. The current study aimed to evaluate the risk of death among users of aclidinium and other LAMAs. METHODS: We conducted a cohort and nested case-control study among patients with COPD aged 40 years or older to compare the risk of all-cause mortality among users of aclidinium and other COPD medications with the risk among users of long-acting ß2 agonists (LABA), in the Clinical Practice Research Datalink (CPRD) in the United Kingdom (2012-2017). RESULTS: Mortality rates per 1,000 person-years were 32.9 for aclidinium, 43.8 for tiotropium, 38.0 for other LAMA, 47.1 for LABA/ICS, and 38.1 for LABA. The RR of death compared with current use of LABA was 0.54 (confidence interval [95% CI], 0.40-0.72) for aclidinium, 0.96 (95% CI, 0.76-1.21) for tiotropium, 0.76 (95% CI, 0.58-0.99) for other LAMA, and 1.08 (95% CI, 0.90-1.31) for LABA/ICS. Decreased risk for death observed among users of aclidinium was driven by overall current single use (RR = 0.41; 95% CI, 0.22-0.79), which corresponded to 26% of the aclidinium users (<15 cases) and not by multiple use (RR = 1.02; 95% CI, 0.71-1.48). CONCLUSION: Use of aclidinium, tiotropium, other LAMA, or LABA/ICS was not associated with an increased risk of all-cause mortality as compared with the use of LABAs.

Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries: A Cohort and Nested Case-Control Study Using Automated Health Data Sources.

BACKGROUND: Agomelatine is a melatonin receptor agonist and serotonin 5-HT2C receptor antagonist indicated for depression in adults. Hepatotoxic reactions like acute liver injury (ALI) are an identified risk in the European risk management plan for agomelatine. Hepatotoxic reactions have been reported for other antidepressants, but population studies quantifying these risks are scarce. Antidepressants are widely prescribed, and users often have risk factors for ALI (e.g. metabolic syndrome). OBJECTIVE: The goal was to estimate the risk of ALI associated with agomelatine and other antidepressants (fluoxetine, paroxetine, sertraline, escitalopram, mirtazapine, venlafaxine, duloxetine, and amitriptyline) when compared with citalopram in routine clinical practice. METHOD: A nested case-control study was conducted using data sources in Denmark, Germany, Spain, and Sweden (study period 2009-2014). Three ALI endpoints were defined using International Classification of Diseases (ICD) codes: primary (specific codes) and secondary (all codes) endpoints used only hospital discharge codes; the tertiary endpoint included both inpatient and outpatient settings (all codes). Validation of endpoints was implemented. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for current use were estimated for each data source and combined. RESULTS: We evaluated 3,238,495 new antidepressant and 74,440 agomelatine users. For the primary endpoint, the OR for agomelatine versus citalopram was 0.48 (CI 0.13-1.71). Results were also < 1 when no exclusion criteria were applied (OR 0.37; CI 0.19-0.74), when all exclusion criteria except alcohol and drug abuse were applied (OR 0.47; CI 0.20-1.07), and for the secondary (OR 0.40; CI 0.05-3.11) and tertiary (OR 0.79; CI 0.50-1.25) endpoints. Regarding other antidepressants versus citalopram, most OR point estimates were also below one, although with varying widths of the 95% CIs. The result of the tertiary endpoint and the sensitivity analyses of the primary endpoint were the most precise. CONCLUSION: In this study, using citalopram as a comparator, agomelatine was not associated with an increased risk of ALI hospitalisation. The results for agomelatine should be interpreted in the context of the European risk minimisation measures in place. Those measures may have induced selective prescribing and could explain the lower risk of ALI for agomelatine when compared with citalopram. Most other antidepressants evaluated had ORs suggesting a lower risk than citalopram, but additional studies are required to confirm or refute these results.

GOLD assessment of COPD severity in the Clinical Practice Research Datalink (CPRD).

PURPOSE: To evaluate availability of spirometry and symptom data in the Clinical Practice Research Datalink (United Kingdom) to assess COPD severity using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016 definition and comparing it with an algorithm used in other studies. METHODS: This was a descriptive, noninterventional, secondary database cohort study of patients with COPD aged 40 years or older, who initiated treatment with specific COPD medications. Patients were classified according to COPD severity (1) in GOLD 2016 "ABCD" categories based on symptoms (Medical Research Council dyspnea grade, COPD Assessment Test, breathlessness), percent predicted FEV1, and exacerbation history and (2) as mild, moderate, severe, or very severe based on treatment and exacerbation history. RESULTS: The study included 63 900 patients with COPD aged 40 years or older that were new users of 1 or more COPD medication of interest. Percent predicted FEV1 was available for 80.9% of patients; symptoms for 75.6% of patients. Classification into GOLD 2016 ABCD categories was possible for 75.6% of the patients. The GOLD 2016 ABCD definition classified more patients under the high-risk categories (22.1%, A; 18.8%, B; 21.3%, C; 37.9%, D) than did the adapted algorithm (7.9%, mild; 48.6%, moderate; 42.1%, severe; 1.4%, very severe). CONCLUSION: Using our adaptation of the GOLD 2016 COPD severity classification, the information in the Clinical Practice Research Datalink allowed us to ascertain COPD severity in approximately 75% of patients with COPD. Algorithms that include medication use tend to misclassify patients with the extreme COPD severity categories.

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.

Effectiveness of risk minimization measures for the use of cilostazol in United Kingdom, Spain, Sweden, and Germany.

PURPOSE: The purpose of the study is to evaluate the effectiveness of risk minimization measures-labeling changes and communication to health care professionals-recommended by the European Medicines Agency for use of cilostazol for the treatment of intermittent claudication in Europe. METHODS: Observational study of cilostazol in The Health Improvement Network (United Kingdom), EpiChron Cohort (Spain), SIDIAP (Spain), Swedish National Databases, and GePaRD (Germany). Among new users of cilostazol, we compared the prevalence of conditions targeted by the risk minimization measures in the periods before (2002-2012) and after (2014) implementation. Conditions evaluated were prevalence of smoking, cardiovascular conditions, concurrent use of ≥2 antiplatelet agents, concurrent use of potent CYP3A4/CYP2C19 inhibitors and high-dose cilostazol, early monitoring of all users, and continuous monitoring of users at high cardiovascular risk. RESULTS: We included 22 593 and 1821 new users of cilostazol before and after implementation of risk minimization measures, respectively. After implementation, the frequency of several conditions related to the labeling changes improved in all the study populations: prevalence of use decreased between 13% (EpiChron) and 57% (SIDIAP), frequency of cardiovascular contraindications decreased between 8% (GePaRD) and 84% (EpiChron), and concurrent use of high-dose cilostazol and potent CYP3A4/CYP2C19 inhibitors decreased between 6% (Sweden) and 100% (EpiChron). The frequency of other conditions improved in most study populations, except smoking, which decreased only in EpiChron (48% reduction). CONCLUSIONS: This study indicates that the risk minimization measures implemented by the EMA for the use of cilostazol have been effective in all European countries studied, except for smoking cessation before initiating cilostazol, which remains an area of improvement.

Use of Topical Tacrolimus and Topical Pimecrolimus in Four European Countries: A Multicentre Database Cohort Study.

BACKGROUND: Despite the concerns about a potential increased risk of skin cancer and lymphoma with the use of topical tacrolimus and pimecrolimus, no population-based studies have given an overview of the use of these drugs in Europe. OBJECTIVE: To assess the use of topical tacrolimus and pimecrolimus in children and adults in Europe. METHODS: Multicentre database cohort study comprising data from the Netherlands, Denmark, Sweden and the UK. We analysed users of topical tacrolimus and pimecrolimus starting from the date of first availability (between 2002 and 2003) or start establishment of the prescription database in Sweden (2006) through 2011. Use was assessed separately for children (≤ 18 years) and adults. RESULTS: 32,052 children and 104,902 adults were treated with topical tacrolimus, and 32,125 children and 58,280 adults were treated with topical pimecrolimus. The number of users increased rapidly after first availability, especially for topical tacrolimus. Topical tacrolimus was more frequently used in all countries except Denmark. For both drugs, there was a decrease in users after 2004 in the Netherlands and Denmark and after 2005 in the UK, especially among children. This decrease was largest in Denmark. The decrease in the number of users was temporary for topical tacrolimus, while use remained relatively low for topical pimecrolimus. CONCLUSIONS: The number of topical tacrolimus and pimecrolimus users increased rapidly after regulatory approval. A transient reduction in topical tacrolimus use and a persistent reduction in topical pimecrolimus use was seen after 2004 in the Netherlands and Denmark and after 2005 in the UK.

A cohort study on the risk of lymphoma and skin cancer in users of topical tacrolimus, pimecrolimus, and corticosteroids (Joint European Longitudinal Lymphoma and Skin Cancer Evaluation - JOELLE study).

BACKGROUND: There is a concern that topical tacrolimus and pimecrolimus, indicated for second-line treatment of atopic dermatitis, may increase the risk of lymphoma and skin cancer, particularly in children. OBJECTIVE: The aim of this study was to compare incidence rates (IRs) of lymphoma and skin cancer between new users of topical tacrolimus or pimecrolimus and users of moderate- to high-potency topical corticosteroids (TCSs) and untreated subjects. METHODS: This is a multicenter cohort study with frequency matching by strata of propensity scores in population databases in the Netherlands, Denmark, Sweden, and the UK. IR ratios (IRRs) were estimated using Mantel-Haenszel methods for stratified analysis. RESULTS: We included 19,948 children and 66,127 adults initiating tacrolimus, 23,840 children and 37,417 adults initiating pimecrolimus, 584,121 users of TCSs, and 257,074 untreated subjects. IRs of lymphoma per 100,000 person-years were 10.4 events in children and 41.0 events in adults using tacrolimus and 3.0 events in children and 27.0 events in adults using pimecrolimus. The IRR (95% confidence interval [CI]) for lymphoma, tacrolimus versus TCSs, was 3.74 (1.00-14.06) in children and 1.27 (0.94-1.71) in adults. By lymphoma type, the highest IRR was 3.17 (0.58-17.23) for Hodgkin lymphoma in children and 1.76 (95% CI, 0.81-3.79) for cutaneous T-cell lymphoma (CTCL) in adults. For pimecrolimus versus TCSs, the highest IRR was 1.31 (95% CI, 0.33-5.14) for CTCL in adults. Compared with untreated subjects, adults using TCSs had a higher incidence of CTCL (IRR, 10.66; 95% CI, 2.60-43.75). Smaller associations were found between tacrolimus and pimecrolimus use and the risk of malignant melanoma or nonmelanoma skin cancer. CONCLUSION: Use of topical tacrolimus and pimecrolimus was associated with an increased risk of lymphoma. The low IRs imply that even if the increased risk is causal, it represents a small excess risk for individual patients. Residual confounding by severity of atopic dermatitis, increased monitoring of severe patients, and reverse causation could have affected the results.

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.

Risk of acute liver injury associated with the use of moxifloxacin and other oral antimicrobials: a retrospective, population-based cohort study.

STUDY OBJECTIVE: To estimate the incidence and relative risk of a hospitalization or emergency visit for noninfectious liver injury in users of eight oral antimicrobials-amoxicillin, amoxicillin-clavulanic acid, clarithromycin, cefuroxime, doxycycline, levofloxacin, moxifloxacin, telithromycin-compared with nonusers of these antimicrobials. DESIGN: Retrospective, observational cohort study with a nested case-control analysis. DATA SOURCE: HealthCore Integrated Research Database. PATIENTS: Adults with continuous health plan enrollment for at least 6 months before study entry who had a new dispensing of a study antimicrobial between July 1, 2001, and March 31, 2009. Cases had diagnoses indicating noninfectious liver injury during follow-up. To control for potentially confounding risk factors, 10 controls at risk for liver injury during follow-up were matched to each case by age, sex, and event date (liver injury date of the case), and analyses were adjusted for medical history, concomitant drugs, and health care service use. MEASUREMENTS AND MAIN RESULTS: Two physician reviewers (blind to exposure) validated the cases. Among 1.3 million antimicrobial users, we identified 607 cases of liver injury, including 82 cases of severe hepatocellular injury and 11 cases of liver failure. Liver injury incidence in nonusers of study antimicrobials was 35/100,000 person-years (95% confidence interval [CI] 29-42/100,000 person-years). For valid cases, the adjusted relative risk among current users of multiple antimicrobials was 3.2 (95% CI 1.6-6.7). Levofloxacin had the highest relative risk for current single use (3.2, 95% CI 1.8-5.8). Relative risks were also elevated for amoxicillin-clavulanic acid (2.5, 95% CI 1.3-5.0), doxycycline (2.5, 95% CI 1.2-5.2), moxifloxacin (2.3, 95% CI 1.1-4.7), and amoxicillin (2.3, 95% CI 1.1-4.7). CONCLUSION: The results support a comparatively high adjusted relative risk of liver injury among patients exposed concurrently to multiple antimicrobials and modest elevations in the risk for several antimicrobials used alone; however, we found little evidence of any strong effect of commonly used antimicrobials on the risk of liver injury.

Validation of acute liver injury cases in a population-based cohort study of oral antimicrobial users.

We conducted a cohort study of acute, noninfectious liver injury among oral antimicrobial users. Potential cases were identified in the HealthCore Integrated Research Database (HIRD(SM)) population between July 1, 2001, and March 31, 2009, using ICD-9-CM codes primarily for acute and subacute necrosis of the liver, hepatic coma, and unspecified hepatitis. Liver test results were used to confirm case status according to published criteria. Two physician reviewers experienced in studying acute liver injury (blinded to study drug exposures) evaluated data abstracted from hospital and emergency department records to validate potential cases. Of 715 potential cases having claims associated with any of the primary screening codes, 312 (44%) were valid cases, 108 (15%) were not cases, and 295 (41%) were of uncertain status (records inadequate for validation). Among potential cases with adequate medical records, the PPV for presence of any of the primary codes was 74% (95% CI, 70%-78%). The highest PPV for a single code was for acute and subacute necrosis of the liver (84%; 95% CI, 77%-90%). Evaluation of cases of noninfectious liver injury using hospital and emergency department medical records continues to represent the preferred approach in studies using insurance claims data.

Accuracy of International Classification of Diseases, 9th Revision, Clinical Modification codes for upper gastrointestinal complications varied by position and age: a validation study in a cohort of nonsteroidal anti-inflammatory drugs users in Friuli Venezia Giulia, Italy.

PURPOSE: To validate the International Classification of Diseases, 9th Revision, Clinical Modification discharge codes used to identify cases of upper gastrointestinal complications (UGICs) in hospitals of Friuli Venezia Giulia, Italy. METHODS: Cohort study on the risk of UGIC in users of nonsteroidal anti-inflammatory drugs conducted in Friuli Venezia Giulia between 2001 and 2008. Cases were identified through primary and secondary International Classification of Diseases, 9th Revision Clinical specific codes 531 (gastric ulcer), 532 (duodenal ulcer), 533 (peptic ulcer), 534 (gastrojejunal ulcer), and nonspecific code 578 (gastrointestinal hemorrhage). Potential cases were confirmed through hospital chart review. RESULTS: The chart retrieval percentage was 98.4%.The positive predictive value (PPV) was 94.3% for primary codes 531 and 532, 79.5% for code 533, 83.1% for code 534, 40.2% for code 578. The PPV for secondary codes was 34.7% but increased to 88.9% and 79.2% when the primary code was for peritonitis or acute post-hemorrhagic anemia, respectively. Validation of secondary codes increased case ascertainment by 4.9%. Endoscopy confirmed 79.4% of cases but only 67.2% of those above age 84 years. CONCLUSIONS: The PPV was high for specific primary codes and moderate to low for nonspecific primary and secondary codes. The inclusion of confirmed cases identified by nonspecific and secondary codes can be of value in studies that need a complete ascertainment of cases occurring in the study population. In this cohort, not including these cases would underestimate the incidence of UGICs. A potential for case misclassification exists in particular in eldest ages.

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.

Risk of upper gastrointestinal complications in a cohort of users of nimesulide and other nonsteroidal anti-inflammatory drugs in Friuli Venezia Giulia, Italy.

PURPOSE: Information on the risk of upper gastrointestinal complications (UGIC) in users of nimesulide, the most used nonsteroidal anti-inflammatory drug (NSAID) in Italy, is scarce. In the context of the European regulatory review on nimesulide, we estimated and compared the risk associated with nimesulide and other individual NSAIDs with the risk in nonusers. METHODS: We used 2001-2008 data from regional health databases in Friuli Venezia Giulia (FVG), Italy, to conduct a cohort and nested case-control study of users of NSAIDs. Cases were identified by specific and nonspecific hospital discharge diagnoses in primary and secondary position and validated through hospital records. Ten controls per case were selected using density-based sampling from the cohort. Conditional logistic regression was used to estimate adjusted relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: The cohort included 588,827 NSAIDs users and 3031 UGIC cases. Nonspecific codes contributed to 23% of cases and secondary codes to 5%. Among current users, IR per 1000 person-years decreased from 4.45 cases in 2001 to 2.21 cases in 2008. The RR (95%CI) for current use of NSAIDs was 3.28 (2.86, 3.76). RR was <2 for rofecoxib, celecoxib, and nimesulide; 2 to <5 for naproxen, ibuprofen, diclofenac, etoricoxib, and meloxicam; and ≥ 5 for ketoprofen, piroxicam, and ketorolac. CONCLUSIONS: IRs of UGIC in FVG decreased about 50% between 2001 and 2008. Nimesulide was in the low-medium range of RR. A complete ascertainment of UGIC cases in databases may require validation of nonspecific codes, secondary codes, and additional codes such as peritonitis and acute posthemorrhagic anemia.

Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project).

BACKGROUND: The risk of upper gastrointestinal (GI) complications associated with the use of NSAIDs is a serious public health concern. The risk varies between individual NSAIDs; however, there is little information on the risk associated with some NSAIDs and on the impact of risk factors. These data are necessary to evaluate the benefit-risk of individual NSAIDs for clinical and health policy decision making. Within the European Community's Seventh Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (NSAIDs) [SOS] project aims to develop decision models for regulatory and clinical use of individual NSAIDs according to their GI and cardiovascular safety. OBJECTIVE: The aim of this study was to conduct a systematic review and meta-analysis of observational studies to provide summary relative risks (RR) of upper GI complications (UGIC) associated with the use of individual NSAIDs, including selective cyclooxygenase-2 inhibitors. METHODS: We used the MEDLINE database to identify cohort and case-control studies published between 1 January 1980 and 31 May 2011, providing adjusted effect estimates for UGIC comparing individual NSAIDs with non-use of NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual NSAIDs overall and by dose using fixed- and random-effects methods. Subgroup analyses were conducted to evaluate methodological and clinical heterogeneity between studies. RESULTS: A total of 2984 articles were identified and 59 were selected for data abstraction. After review of the abstracted information, 28 studies met the meta-analysis inclusion criteria. Pooled RR ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone. RR was less than 2 for aceclofenac, celecoxib (RR 1.45; 95% CI 1.17, 1.81) and ibuprofen (RR 1.84; 95% CI 1.54, 2.20); 2 to less than 4 for rofecoxib (RR 2.32; 95% CI 1.89, 2.86), sulindac (RR 2.89; 95% CI 1.90, 4.42), diclofenac (RR 3.34; 95% CI 2.79, 3.99), meloxicam (RR 3.47; 95% CI 2.19, 5.50), nimesulide (RR 3.83; 95% CI 3.20, 4.60) and ketoprofen (RR 3.92; 95% CI 2.70, 5.69); 4-5 for tenoxicam (RR 4.10; 95% CI 2.16, 7.79), naproxen (RR 4.10; 95% CI 3.22, 5.23), indometacin (RR 4.14; 95% CI 2.91, 5.90) and diflunisal (RR 4.37; 95% CI 1.07, 17.81); and greater than 5 for piroxicam (RR 7.43; 95% CI 5.19, 10.63), ketorolac (RR 11.50; 95% CI 5.56, 23.78) and azapropazone. RRs for the use of high daily doses of NSAIDs versus non-use were 2-3 times higher than those associated with low daily doses. CONCLUSIONS: We confirmed variability in the risk of UGIC among individual NSAIDs as used in clinical practice. Factors influencing findings across studies (e.g. definition and validation of UGIC, exposure assessment, analysis of new vs prevalent users) and the scarce data on the effect of dose and duration of use of NSAIDs and on concurrent use of other medications need to be addressed in future studies, including SOS.

Clinical burden and incremental cost of fractures in postmenopausal women in the United Kingdom.

This cohort study of postmenopausal women in the United Kingdom aged ≥50years determined the incremental cost of health care and clinical outcomes in the 12months following incident, selected fractures (non-vertebral non-hip [NVNHF], vertebral [VF] and multiple [MF]). Incremental costs and outcomes of the fracture cohorts were compared with those of cohorts comprised of women without fractures who were individually matched on age and comorbidity. Cohorts were identified from The Health Improvement Network database, a primary health care database, from 2001 to 2005. We estimated 1-year incremental costs (hospitalizations; general practice, accident/emergency, and referral visits; and prescription medications) associated with each fracture type. Descriptive analyses examined occurrence of subsequent fractures and death. No long-term health care costs or outcomes were assessed. Overall, 14,030 women had NVNHF, 1471 had VF, and 193 had MF. The risk of death was greater for women with fractures than for women in the non-fracture cohorts. Mean incremental cost for fractures compared with no fractures was £1152 for VF; £690 for NVNHF, and £2581 for MF. Of the total incremental cost, hospitalizations represented 54%-90% and medications represented 7%-29%. In all fracture cohorts, most of the total annual costs were concentrated in the 6months after the date of fracture. Fractures among postmenopausal women represent an important burden to the health system due to the increase in health resource utilization and related costs. In this study, hospitalizations were the main driver of the overall incremental cost during the 12months following the fracture. Mortality in women in the selected fracture cohorts was higher than in women in the non-fracture cohorts.

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.

Study of the incremental cost and clinical burden of hip fractures in postmenopausal women in the United Kingdom.

OBJECTIVE: To determine the incremental cost of healthcare and clinical outcomes in the 12 months following incident hip fractures among postmenopausal women in the UK. METHODS: Retrospective cohort study of women aged 50 years or older hospitalized for an incident hip fracture within 1 week of the fracture date who were age- and comorbidity-matched to women without fracture. Cohorts were identified in the Health Improvement Network database, and followed up for 1 year. RESULTS: Among 2,427 women who had a hip fracture and a recorded hospitalization, the mean [SD] age was 81 [9.3] years. About 18% of women without fractures were hospitalized during follow-up and 18% of women with hip fractures and 4% of women without fractures had at least one emergency admission (RR, 4.7; 95% CI, 3.8-5.8). There were no major differences in use of general practitioner visit, referral visits, or in prescription of medications. Mortality was 18% in the hip fracture cohort and 7% in the non-fracture cohort (RR, 2.5; 95% CI, 2.1-3.0). The overall 1-year mean incremental cost of hip fractures was £4,222 (95% CI, £4,105-4,339); most of this cost (97%) was for hospitalizations, with an increment of £4,095. About 98% of the incremental cost occurred in the first 6 months following hip fracture. CONCLUSIONS: The results of this study indicate that the cost and clinical burden associated with hip fractures in postmenopausal women in the UK are considerable. The incremental cost is mostly related to the cost of hospitalization and treatment of the hip fracture. Key limitations were the inclusion of only those women with a recorded hospitalization, and that costs associated with rehabilitation services, social services, and long-term care were not recorded in this study, although these are important contributors to the total cost of fractures.

Use of long-acting beta-agonists and inhaled steroids in asthma: meta-analysis of observational studies.

BACKGROUND: Current asthma guidelines recommend the use of long-acting beta-agonists (LABAs) in combination with inhaled corticosteroids (ICSs) for long-term control and prevention of symptoms in persistent asthma. Data on the risk of asthma exacerbations of LABAs in combination with ICSs, as prescribed in typical clinical practice, are very scarce. METHODS: The authors conducted a systematic literature review and meta-analysis of observational studies to examine the risk of asthma exacerbations, measured as asthma-related hospitalization and/or asthma-related emergency room (ER) visits, in adults receiving LABAs plus ICSs in a fixed-dose combination compared with patients receiving ICSs alone. RESULTS: Seven studies, all retrospective cohort studies conducted in the United States, representing approximately 96,000 patients, were included in the meta-analysis. The meta-analysis found that the use of ICSs plus LABAs was associated with a lower risk of asthma-related hospitalizations and/or ER visits than ICSs alone (odds ratio: 0.82; 95% confidence interval: 0.72-0.94). Sensitivity analyses to explore heterogeneity of endpoint definition, duration of follow-up, and patient characteristics did not significantly alter the findings. CONCLUSIONS: Overall, this systematic meta-analysis suggests that patients in clinical practice treated with a single inhaler containing ICSs plus LABAs experience fewer asthma exacerbations than similar patients treated with ICSs alone.