No abstract

No abstract

ObjeCtivesTo investigate the cardiovascular safety of nonsteroidal anti-inflammatory drugs (NSAIDs) and estimate the risk of hospital admission for heart failure with use of individual NSAIDs. DesignNested case-control study.setting Five population based healthcare databases from four European countries (the Netherlands, Italy, Germany, and the United Kingdom). PartiCiPantsAdult 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 MeasureAssociation 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.

No abstract

ObjectiveTo evaluate positive predictive value (PPV) of different disease codes and free text in identifying acute myocardial infarction (AMI) from electronic healthcare records (EHRs).DesignValidation study of cases of AMI identified from general practitioner records and hospital discharge diagnoses using free text and codes from the International Classification of Primary Care (ICPC), International Classification of Diseases 9th revision-clinical modification (ICD9-CM) and ICD-10th revision (ICD-10).SettingPopulation-based databases comprising routinely collected data from primary care in Italy and the Netherlands and from secondary care in Denmark from 1996 to 2009.ParticipantsA total of 4 034 232 individuals with 22 428 883 person-years of follow-up contributed to the data, from which 42 774 potential AMI cases were identified. A random sample of 800 cases was subsequently obtained for validation.Main outcome measuresPPVs were calculated overall and for each code/free text. ‘Best-case scenario’ and ‘worst-case scenario’ PPVs were calculated, the latter taking into account non-retrievable/non-assessable cases. We further assessed the effects of AMI misclassification on estimates of risk during drug exposure.ResultsRecords of 748 cases (93.5% of sample) were retrieved. ICD-10 codes had a ‘best-case scenario’ PPV of 100% while ICD9-CM codes had a PPV of 96.6% (95% CI 93.2% to 99.9%). ICPC codes had a ‘best-case scenario’ PPV of 75% (95% CI 67.4% to 82.6%) and free text had PPV ranging from 20% to 60%. Corresponding PPVs in the ‘worst-case scenario’ all decreased. Use of codes with lower PPV generally resulted in small changes in AMI risk during drug exposure, but codes with higher PPV resulted in attenuation of risk for positive associations.ConclusionsICD9-CM and ICD-10 codes have good PPV in identifying AMI from EHRs; strategies are necessary to further optimise utility of ICPC codes and free-text search. Use of specific AMI disease codes in estimation of risk during drug exposure may lead to small but significant changes and at the expense of decreased precision.

Na(+)/H(+) exchanger 3 (NHE3) is expressed in the brush border (BB) of intestinal epithelial cells and accounts for the majority of neutral NaCl absorption. It has been shown that the Na(+)/H(+) exchanger regulatory factor (NHERF) family members of multi-PDZ domain-containing scaffold proteins bind to the NHE3 COOH terminus and play necessary roles in NHE3 regulation in intestinal epithelial cells. Most studies of NHE3 regulation have been in cell models in which NHERF1 and/or NHERF2 were overexpressed. We have now developed an intestinal Na(+) absorptive cell model in Caco-2/bbe cells by expressing hemagglutinin (HA)-tagged NHE3 with an adenoviral infection system. Roles of NHERF1 and NHERF2 in NHE3 regulation were determined, including inhibition by cAMP, cGMP, and Ca(2+) and stimulation by EGF, with knockdown (KD) approaches with lentivirus (Lenti)-short hairpin RNA (shRNA) and/or adenovirus (Adeno)-small interfering RNA (siRNA). Stable infection of Caco-2/bbe cells by NHERF1 or NHERF2 Lenti-shRNA significantly and specifically reduced NHERF protein expression by >80%. NHERF1 KD reduced basal NHE3 activity, while NHERF2 KD stimulated NHE3 activity. siRNA-mediated (transient) and Lenti-shRNA-mediated (stable) gene silencing of NHERF2 (but not of NHERF1) abolished cGMP- and Ca(2+)-dependent inhibition of NHE3. KD of NHERF1 or NHERF2 alone had no effect on cAMP inhibition of NHE3, but KD of both simultaneously abolished the effect of cAMP. The stimulatory effect of EGF on NHE3 was eliminated in NHERF1-KD but occurred normally in NHERF2-KD cells. These findings show that both NHERF2 and NHERF1 are involved in setting NHE3 activity. NHERF2 is necessary for cGMP-dependent protein kinase (cGK) II- and Ca(2+)-dependent inhibition of NHE3. cAMP-dependent inhibition of NHE3 activity requires either NHERF1 or NHERF2. Stimulation of NHE3 activity by EGF is NHERF1 dependent.

Background Gastro-protective agents (GPA) are co-prescribed with non-steroidal anti-inflammatory drugs (NSAID) to lower the risk of upper gastrointestinal (UGI) events. It is unknown to what extent the protective effect is influenced by therapy adherence. Aim To study the association between GPA adherence and UGI events among non-selective (ns) NSAID users. Methods The General Practice Research Database (UK 1998e2008), the Integrated Primary Care Information database (the Netherlands 1996e2007) and the Health Search/CSD Longitudinal Patient Database (Italy 2000e2007) were used. A nested case-control design was employed within a cohort of nsNSAID users aged $50 years, who also used a GPA. UGI event cases (UGI bleeding and/or symptomatic ulcer with/without obstruction/perforation) were matched to event-free members of the cohort for age, sex, database and calendar time. Adherence to GPA was calculated as the proportion of nsNSAID treatment days covered by a GPA prescription. Adjusted OR with 95% CI were calculated. Results The cohort consisted of 618 684 NSAID users, generating 1 107 266 nsNSAID episodes. Of these, 117 307 (10.6%) were (partly) covered by GPA, 4.9% of which with a GPA coverage <20% (non-adherence), and 68.1% with a GPA coverage >80% (full adherence). 339 patients experienced an event. Among non-adherers, the OR was 2.39 (95% CI 1.66 to 3.44) for all UGI events and 1.89 (95% CI 1.09 to 3.28) for UGI bleeding alone, compared to full adherers. Conclusions The risk of UGI events was significantly higher in nsNSAID users with GPA non-adherence. This underlines the importance of strategies to improve GPA adherence.Non-steroidal anti-inflammatory drugs (NSAID) have analgesic and anti-inflammatory properties, and are indicated mainly for pain management in musculoskeletal injury, osteoarthritis and rheumatoid arthritis. The use of NSAID may lead to upper gastrointestinal (UGI) symptoms such as dyspepsia, and to more severe events such as gastroduodenal ulcers or UGI bleeding. The incidence of such clinically significant UGI events during NSAID use has been estimated at 1e2.5/100 person-years 1 2 and is associated with substantial mortality.3 Non-selective (ns) NSAID inhibit the cyclooxygenase 1 enzyme more strongly than cyclooxygenase 2 selective inhibitors. 4 As cyclooxygenase 1 is involved in gastroprotection, nsNSAID are believed to increase the risk of UGI events to a higher degree than cyclooxygenase 2 inhibitors. 5To prevent UGI events during nsNSAID use, evidence-based guidelines recommend the concomitant use of gastroprotective agents (GPA), 6 mostly in nsNSAID users with one or more risk factors. The guidelines differ slightly in their definition of risk factors, but most consider advanced age, the history of a UGI event and the use of antiplatelet agents, anticoagulants or corticosteroids as risk factors.7e9 Some guidelines also mention other factors, including the use of selective serotonin Significance of this study What is already known about this subject?< The use of non-selective no...

No abstract