Giuseppe Traversa

Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs

Abstract Objective To estimate the risk of acute hepatotoxicity associated with nimesulide compared with other non-steroidal anti-inflammatory drugs. Design Retrospective cohort and nested case-control study. Setting Umbria region, Italy. Participants 400 000 current, recent, and past users (almost 2 million prescriptions) of non-steroidal anti-inflammatory drugs between 1 January 1997 and 31 December 2001. Main outcome measures Admissions to hospital for acute non-viral hepatitis and incidence of all hepatopathies and liver injury among users of nimesulide and other non-steroidal anti-inflammatory drugs. Results Current use of non-steroidal anti-inflammatory drugs was associated with a 1.4 (95% confidence interval 1.0 to 2.1) increased risk of hepatopathy compared with past use. In current users of nimesulide the rate ratio for all hepatopathies and more severe liver injury was 1.3 (0.7 to 2.3) and 1.9 (1.1 to 3.8), respectively. Conclusion The risk of liver injury in patients taking nimesulide and other non-steroidal anti-inflammatory drugs is small.

Gastroduodenal toxicity of different nonsteroidal antiinflammatory drugs.

Although the etiologic relation between nonsteroidal antiinflammatory drug (NSAID) use and gastrointestinal lesions is well documented, newly introduced NSAIDs deserve a fresh examination for their risk/benefit ratio. To estimate the association between consumption of ketorolac and the occurrence of gastroduodenal lesions, we conducted a case-control study. The study population comprised 600 outpatients with a confirmed endoscopic diagnosis of ulcer and erosion in 1991 and 1992 and 6,000 community controls matched by age and sex. We retrieved the prescription history through a computerized prescription monitoring system. We defined exposure to each study drug as “current” (month of endoscopy and preceding month), “recent” (second or third month preceding endoscopy), and “past” (fourth to sixth month preceding endoscopy). Current users of NSAIDs showed a 30% increase in the incidence of gastroduodenal lesions [odds ratio (OR) = 1.3; 95% confidence interval (CI) = 0.98–1.8] after adjustment for recent or past use of any NSAID, recent or past gastrotoxic therapy, recent or past use of gastroprotective drugs, and recent or past use of any other drug. Among NSAIDs, ketorolac was the only one showing a distinctly elevated risk of gastroduodenal lesions (OR = 4.2; 95% CI = 1.9–9.4). Current use of any NSAID was associated with almost a doubling of risk for ulcer alone (OR = 1.9; 95% CI = 1.3–3.0); no elevation in risk was found for erosions. The adjusted relative risk for ulcer associated with current use of ketorolac was 9.8 (95% CI = 3.4–28.1). Recent and past use of NSAIDs does not increase the risk of ulcer. The use of ketorolac appears to carry a greater gastrotoxicity than other NSAIDs.

Off-label use of medicines in children: can available evidence avoid useless paediatric trials?

PurposeIn some cases of drug therapy, the available evidence might be sufficient to extend the indications to children without further clinical studies.MethodsWe reviewed the available evidence for one of the categories of drugs most frequently used off-label in children: proton pump inhibitors (PPIs) used for the treatment of gastroesophageal reflux disease (GERD). A classification of the appropriateness of off-label use of PPIs in children with GERD was also performed.ResultsOf the five PPIs evaluated, only omeprazole has a paediatric indication in Europe. Overall, 19 clinical trials were retrieved and evaluated on the basis of pharmacokinetics, efficacy and safety data. The off-label use of omeprazole, esomeprazole and lansoprazole in children was evaluated as appropriate given the consistent available evidence retrieved in literature.ConclusionThis study demonstrates the existence of a large body of clinical evidence on the use of PPIs in children. Regulatory agencies and ethical committees should cope with this issue for ethical reasons to avoid unnecessary trial replication.

The geographic relationship between the use of antimicrobial drugs and the pattern of resistance for Streptococcus pneumoniae in Italy

ObjectivesA temporal relationship between the increasing use of antibiotics and the increasing levels of antibiotic resistance has been established for Streptococcus pneumoniae. There are also data that support the presence of a geographic correlation between the level of resistance and the pattern of use among different countries and even within the same country. The aim of this study was to evaluate the potential geographic correlation between the use of β-lactams and erythromycin in different Italian regions and the resistance of these antibiotics to invasive strains of S. pneumoniae during the period 1999–2000.MethodsEcological studyResultsIn Italy the mean level of resistance for penicillin and erythromycin was 11.4% and 28.9%, respectively. The highest level of resistance for both antibiotics was observed in central and southern regions (i.e. Campania, Lazio and the combined regions of Calabria, Puglia and Sicilia). These regions were also those with the highest consumption of antibiotics. A strong correlation was found between the prevalence of resistance to erythromycin and the regional use of macrolides (r=0.93, P=0.001) and β-lactams (r=0.84, P=0.002). With regard to penicillin resistance, the greatest correlation was observed for oral penicillin (r=0.85, P=0.002).ConclusionOur study provides further evidence of the association between regional level of antibiotic use and prevalence of antibiotic resistance.

Feasibility and challenges of independent research on drugs: the Italian medicines agency (AIFA) experience

Eur J Clin Invest 2010; 40 (1): 69–86

Gangliosides and Guillain-Barré syndrome

Cases of Guillain-Barré syndrome (GBS) associated with parenteral use of gangliosides have been reported in several European countries. To evaluate the hypothesis of association between ganglioside exposure and occurrence of GBS, a case-control study was conducted. GBS cases discharged during 1989 from public and private hospitals in three Italian provinces were identified: 42 GBS cases and 420 controls matched on age and gender were enrolled. Data of onset of symptoms of GBS was taken from clinical records. Exposure status of subjects was ascertained through the regional computerized drug prescription monitoring system. The odds ratio of association between ganglioside use, in the 30 days prior to onset of symptoms, and GBS was 9.1 (95% confidence interval 2.8-29.4). Although there are formidable difficulties in distinguishing prodromal therapy of GBS from drug causation, the association with ganglioside therapy is strong and supportive of the hypothesis of a role of ganglioside preparations in the occurrence of GBS.

Ketorolac use in outpatients and gastrointestinal hospitalization: a comparison with other non-steroidal anti-inflammatory drugs in Italy

AbstractObjective: To compare the risk of hospitalization for gastroduodenal ulcer associated with the use of ketorolac and other non-steroidal anti-inflammatory drugs (NSAIDs). Methods: A cohort and a nested case-control study were carried out. All residents in the region of Umbria (Italy), aged 35–84 years, who had been given at least one NSAID prescription in 1993 and 1994 were identified. Exposure to drugs was ascertained through a drug prescription database. We estimated rate ratios of hospitalization for gastroduodenal ulcer with or without complications in the current, recent or past period according to exposure to different NSAIDs. Results: Rate ratio estimates, adjusted for age and sex, were 2.8 for any current NSAID and 1.4 for any recent NSAID. The highest rate ratios of lesions of any severity for current NSAID use were observed for piroxicam (RR: 4.6) and ketorolac (RR: 3.4). For gastrointestinal haemorrhage or perforation the highest rate ratios were those for ketorolac (RR: 5.9) and piroxicam (RR: 4.8). Rate ratio estimates did not change after adjustment for concomitant use of gastrotoxic drugs, use of gastroprotective agents not associated with NSAIDs and prior use of NSAIDs. Conclusion: Our study demonstrates the need to adhere to the restrictions relating to the indications and duration of use of ketorolac. At present piroxicam represents a greater public health concern since it is confirmed to be among the most gastrotoxic NSAIDs and is one of the most commonly prescribed NSAIDs in Italy.

Evaluation of safety of A/H1N1 pandemic vaccination during pregnancy: cohort study.

Objective To assess the risk of maternal, fetal, and neonatal outcomes associated with the administration of an MF59 adjuvanted A/H1N1 vaccine during pregnancy. Design Historical cohort study. Setting Singleton pregnancies of the resident population of the Lombardy region of Italy. Participants All deliveries between 1 October 2009 and 30 September 2010. Data on exposure to A/H1N1 pandemic vaccine, pregnancy, and birth outcomes were retrieved from regional databases. Vaccinated and non-vaccinated women were compared in a propensity score matched analysis to estimate risks of adverse outcomes. Main outcome measures Main maternal outcomes included type of delivery, admission to intensive care unit, eclampsia, and gestational diabetes; fetal and neonatal outcomes included perinatal deaths, small for gestational age births, and congenital malformations. Results Among the 86 171 eligible pregnancies, 6246 women were vaccinated (3615 (57.9%) in the third trimester and 2557 (40.9%) in the second trimester). No difference was observed in terms of spontaneous deliveries (adjusted odds ratio 1.02, 95% confidence interval 0.96 to 1.08) or admissions to intensive care units (0.95, 0.47 to 1.88), whereas a limited increase in the prevalence of gestational diabetes (1.26, 1.04 to 1.53) and eclampsia (1.19, 1.04 to 1.39) was seen in vaccinated women. Rates of fetal and neonatal outcomes were similar in vaccinated and non-vaccinated women. A slight increase in congenital malformations, although not statistically significant, was present in the exposed cohort (1.14, 0.99 to 1.31). Conclusions Our findings add relevant information about the safety of the MF59 adjuvanted A/H1N1 vaccine in pregnancy. Residual confounding may partly explain the increased risk of some maternal outcomes. Meta-analysis of published studies should be conducted to further clarify the risk of infrequent outcomes, such as specific congenital malformations.

Drug use and acute leukemia.

Objective—To study the occurrence of acute leukemia in relation to preceding use of drugs a case–control study has been carried out in Rome, Italy.

Drug use and upper gastrointestinal complications in children: a case-control study

Objective To evaluate the risk of upper gastrointestinal complications (UGIC) associated with drug use in the paediatric population. Methods This study is part of a large Italian prospective multicentre study. The study population included children hospitalised for acute conditions through the emergency departments of eight clinical centres. Patients admitted for UGIC (defined as endoscopically confirmed gastroduodenal lesions or clinically defined haematemesis or melena) comprised the case series; children hospitalised for neurological disorders formed the control group. Information on drug and vaccine exposure was collected through parental interview during the childrens hospitalisation. Logistic regression was used to estimate ORs for the occurrence of UGIC associated with drug use adjusted for age, clinical centre and concomitant use of any drug. Results 486 children hospitalised for UGIC and 1930 for neurological disorders were enrolled between November 1999 and November 2010. Drug use was higher in cases than in controls (73% vs 54%; p<0.001). UGICs were associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) (adjusted OR 2.9, 95% CI 2.1 to 4.0), oral steroids (adjusted OR 2.9, 95% CI 1.7 to 4.8) and antibiotics (adjusted OR 2.3, 95% CI 1.8 to 3.1). The duration of use of these drug categories was short (range 1–8 days). Paracetamol showed a lower risk (adjusted OR 2.0, 95% CI 1.5 to 2.6) compared to ibuprofen (adjusted OR 3.7, 95% CI 2.3 to 5.9), although with partially overlapping CIs. Conclusions NSAIDs, oral steroids and antibiotics, even when administered for a short period, were associated with an increased risk of UGIC.