Background: Recently, the use of proton pump inhibitors (PPIs) has been associated with an increased risk of pneumonia. We aimed to confirm this association and to identify the risk factors. Methods: We conducted a population-based casecontrol study using data from the County of Funen, Denmark. Cases (n = 7642) were defined as all patients with a first-discharge diagnosis of community-acquired pneumonia from a hospital during 2000 through 2004. We also selected 34 176 control subjects, who were frequency matched to the cases by age and sex. Data on the use of PPIs and other drugs, on microbiological samples, on x-ray examination findings, and on comorbid conditions were extracted from local registries. Confounders were controlled by logistic regression. Results: The adjusted odds ratio (OR) associating current use of PPIs with community-acquired pneumonia was 1.5 (95% confidence interval [CI], 1.3-1.7). No association was found with histamine 2-receptor antagonists (OR, 1.10; 95% CI, 0.8-1.3) or with past use of PPIs (OR, 1.2; 95% CI, 0.9-1.6). Recent initiation of treatment with PPIs (0-7 days before index date) showed a particularly strong association with communityacquired pneumonia (OR, 5.0; 95% 2.1-11.7), while the risk decreased with treatment that was started a long time ago (OR, 1.3; 95% CI, 1.2-1.4). Subgroup analyses revealed high ORs for users younger than 40 years (OR, 2.3; 95% CI, 1.3-4.0). No dose-response effect could be demonstrated. Conclusion: The use of PPIs, especially when recently begun, is associated with an increased risk of communityacquired pneumonia.

BackgroundMost NSAIDs are thought to be able to cause hepatic injury and acute liver failure (ALF), but the event rates of those leading to transplantation (ALFT) remain uncertain.ObjectivesThe aim of the study was to estimate population event rates for NSAID-associated ALFTMethodsThis was a case-population study of ALFT in 57 eligible liver transplant centres in seven countries (France, Greece, Ireland, Italy, The Netherlands, Portugal and the UK). Cases were all adults registered from 2005 to 2007 for a liver transplant following ALFT without identified clinical aetiology, exposed to an NSAID or paracetamol (acetaminophen) within 30 days before the onset of clinical symptoms. NSAID and paracetamol population exposures were assessed using national sales data from Intercontinental Marketing Services (IMS). Risk was estimated as the rate of ALFT per million treatment-years (MTY).ResultsIn the 52 participating centres, 9479 patients were registered for transplantation, with 600 for ALFT, 301 of whom, without clinical aetiology, had been exposed to a drug within 30 days. Of these 301 patients, 40 had been exposed to an NSAID and 192 to paracetamol (81 of whom were without overdose).Event rates per MTY were 1.59 (95 % CI 1.1–2.2) for all NSAIDs pooled, 2.3 (95 % CI 1.2–3.9) for ibuprofen, 1.9 (95 % CI 0.8–3.7) for nimesulide, 1.6 (95 % CI 0.6–3.4) for diclofenac and 1.6 (95 % CI 0.3–4.5) for ketoprofen. For paracetamol, the event rate was 3.3 per MTY (95 % CI 2.6–4.1) without overdoses and 7.8 (95 % CI 6.8–9.0) including overdoses.ConclusionsALF leading to registration for transplantation after exposure to an NSAID was rare, with no major difference between NSAID. Non-overdose paracetamol-exposed liver failure was twice more common than NSAID-exposed liver failure.Electronic supplementary materialThe online version of this article (doi:10.1007/s40264-012-0013-7) contains supplementary material, which is available to authorized users.

Paracetamol overdose was found to represent one-sixth of all-cause ALFT. There was a 50-fold difference in Europe in the rates of paracetamol overdose ALFT, and a 200-fold difference per million inhabitants.

AIMSThe aim of the present study was to describe the real-life usage patterns of paracetamol. METHODSThe Echantillon Généraliste de Bénéficiaires (EGB) database, the permanent 1/97 representative sample from the French national healthcare insurance system, was searched in 2011 to identify usage patterns, concomitant chronic diseases and use of cardiovascular medication in users prescribed single-ingredient (SP) and combination (CP) paracetamol, representing 85% of all sales. RESULTSOf 526 108 subjects aged ≥15 years in the EGB, 268 725 (51%) had paracetamol dispensed on ≥1 occasion; of these, 207 707 (77%) were dispensed only SP and 61 018 (23%) received CP with or without SP. SP users were younger (48.3 years vs. 50.5 years), and 57% of SP users vs. 58% of CP users were female. Chronic comorbidities were more common in CP than SP users. SP users had, on average, 3.4 dispensings per year vs. 5.0 for CP users, for 36 defined daily doses (DDD, 3 g) of SP vs. 53 DDD per year for CP; 49% SP users bought 14 DDD or fewer; 15% bought >60 DDD. Use of paracetamol increased with age from about 16 DDD per year in 15-30-yearolds to over 90 DDD per year in patients above the age of 75; 53% of patients ≤60 years bought fewer than 14 DDD per year, whereas 55% of those >60 bought more than 30 DDD per year. More than half the dispensings exceeded the legal per-box limit of 8 g. CONCLUSIONSOver 50% of the French adult population were dispensed paracetamol at least once over the course of a year, generally for shortterm use. Considering recent misgivings on the real efficacy and safety of paracetamol, such widespread use might have important public health consequences. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Although paracetamol is used mostly in mild-to-moderate pain conditions and in chronic arthritis, and its usage pattern might be derived from these indications, there are few or no studies of actual usage patterns and drug exposure or burden. WHAT THIS STUDY ADDS• Over 50% of all adults in the database were dispensed paracetamol at least once in 2011.• The median amount of paracetamol dispensed over 1 year was seven defined daily doses (or 21 g), and this increased with age.• Only 15% of subjects received more than 60 days' worth of paracetamol in a year. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2016) 82 498-503 498

ALFT risk with NSAID seems to be user dependent rather than person-time (exposure) dependent. Choosing the wrong denominator in case population studies might give erroneous results.

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• An apparent protective effect of statins against upper gastrointestinal bleeding was postulated in a post hoc analysis of a randomized trial.• We aimed to evaluate the effect of statin use on acute nonvariceal upper gastrointestinal bleeding alone or in combinations with low-dose aspirin and other antithrombotic drugs. WHAT THIS STUDY ADDS• Our study could not demonstrate an inverse association between use of statins and upper gastrointestinal bleeding. • The lack of effect was consistent across most subgroups, across different cumulative or current doses and different statin substances.• In explorative analyses, there appeared to be protective effect only in users of low-dose aspirin.• There was no interaction with use of other antithrombotic drugs. AIMSRecently, an apparent protective effect of statins against upper gastrointestinal bleeding (UGB) was postulated in a post hoc analysis of a randomized trial. We aimed to evaluate the effect of statin use on acute nonvariceal UGB alone or in combinations with low-dose aspirin and other antithrombotic drugs. METHODSA population-based case-control study was conducted in the County of Funen, Denmark. Cases (n = 3652) were all subjects with a first discharge diagnosis of serious UGB from a hospital during the period 1995 to 2006. Age-and gender-matched controls (10 for each case) (n = 36 502) were selected by a risk set sampling. Data on all subjects' drug exposure and past medical history were retrieved from a prescription database and from the County's patient register. Confounders were controlled by conditional logistic regression. RESULTSThe adjusted odds ratios (ORs) associating use of statins with UGB were 0.94 (0.78-1.12) for current use, 1.40 (0.89-2.20) for recent use and 1.42 (0.96-2.10) for past use. The lack of effect was consistent across most patient subgroups, different cumulative or current statin doses and different statin substances. In explorative analyses, a borderline significant protective effect was observed for concurrent users of low-dose aspirin ]. CONCLUSIONStatins do not prevent UGB, except possibly in users of low-dose aspirin.

The present study created a multinational research network to estimate population-based absolute rates of drug-exposed ALF leading to registration on the transplantation list. This study design was chosen to obtain a fast response to a public health issue, namely, that of an increased risk of a rare, very serious adverse reaction. This model could be used to study other drug-related issues in ALF.