Elisabetta Poluzzi

Dipeptidyl peptidase-4 inhibitors and heart failure: Analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System

BACKGROUND AND AIMSnWe tested the possible association between dipeptidyl peptidase-4 inhibitors (DPP-4-I) use and heart failure (HF) occurrence by assessing the publicly available US-FDA Adverse Event Reporting System (FAERS).nnnMETHODSnFAERS data reporting HF and DPP-4-Is use in the period from the fourth quarter of 2006 through 2013 were extracted, using the Standardized MedDRA Query Cardiac failure. Disproportionality (case/non-case method) was implemented by calculating Reporting Odds Ratios (RORs) with 95% Confidence Interval (CI): (1) exploratory analysis on the entire FAERS (using rosiglitazone as positive control); (2) consolidated analyses by therapeutic area (within antidiabetics), correcting for event- and drug-related competition bias and adjusting for co-reported drugs as confounders.nnnRESULTSnHF during DPP4-I use was recorded in 390 reports (4.4% of total reports). In exploratory analysis, statistically significant ROR emerged for DPP-4-I as a class (RORxa0=xa01.17; 95% CIxa0=xa01.05-1.29), saxagliptin (1.68; 1.29-2.17), vildagliptin (2.39; 1.38-4.14), and rosiglitazone (13.98; 13.30-14.70). In consolidated analyses, the ROR for saxagliptin (2.60; 1.92-3.50) and vildagliptin (4.07; 2.28-7.27) increased, and became also significant for sitagliptin (1.61; 1.40-1.86). Concomitant drugs were reported in more than 50% of cases; the adjusted RORs of saxagliptin (2.30; 1.70-3.10), vildagliptin (3.15; 1.76-5.63), and sitagliptin (1.48; 1.28-1.71) were nonetheless significant.nnnCONCLUSIONnFAERS data are consistent with clinical studies on a possible association between saxagliptin and HF. The disproportionate reporting of HF with sitagliptin, conflicting with a recent phase IV trial, suggests that cardiovascular safety requires close post-marketing vigilance by clinicians of individual DPP-4-I in the community until the issue of class effect is solved.

Use of azithromycin and risk of ventricular arrhythmia

BACKGROUND: There are conflicting findings from observational studies of the arrhythrogenic potential of azithromycin. Our aim was to quantify the association between azithromycin use and the risk of ventricular arrhythmia. METHODS: We conducted a nested case–control study within a cohort of new antibiotic users identified from a network of 7 population-based health care databases in Denmark, Germany, Italy, the Netherlands and the United Kingdom for the period 1997–2010. Up to 100 controls per case were selected and matched by age, sex and database. Recency of antibiotic use and type of drug (azithromycin was the exposure of interest) at the index date (occurrence of ventricular arrhythmia) were identified. We estimated the odds of ventricular arrhythmia associated with current azithromycin use relative to current amoxicillin use or nonuse of antibiotics (≥ 365 d without antibiotic exposure) using conditional logistic regression, adjusting for confounders. RESULTS: We identified 14 040 688 new antibiotic users who met the inclusion criteria. Ventricular arrhythmia developed in 12 874, of whom 30 were current azithromycin users. The mean age of the cases and controls was 63 years, and two-thirds were male. In the pooled data analyses across databases, azithromycin use was associated with an increased risk of ventricular arrhythmia relative to nonuse of antibiotics (adjusted odds ratio [OR] 1.97, 95% confidence interval [CI] 1.35–2.86). This increased risk disappeared when current amoxicillin use was the comparator (adjusted OR 0.90, 95% CI 0.48–1.71). Database-specific estimates and meta-analysis confirmed results from the pooled data analysis. INTERPRETATION: Current azithromycin use was associated with an increased risk of ventricular arrhythmia when compared with nonuse of antibiotics, but not when compared with current amoxicillin use. The decreased risk with an active comparator suggests significant confounding by indication.

Prescribing pattern of antipsychotic drugs during the years 1996-2010: a population-based database study in Europe with a focus on torsadogenic drugs.

INTRODUCTIONnAntipsychotic drugs (APDs) are used to treat several mental illnesses. Some APDs have long been known to be associated with QT prolongation, potentially leading to torsades de pointes (TdP) and sudden cardiac death (SCD). In 2005, thioridazine was withdrawn because of the risk of SCD, bringing further attention to the arrhythmogenic potential of APDs.nnnAIMnThe aim of the current study was to evaluate the use of APDs in five European countries during the years 1996-2010.nnnMETHODSnA cohort study was conducted using prescription/dispensing data from seven healthcare databases [the AARHUS University Hospital Database (Denmark), the German Pharmacoepidemiological Research Database (GePaRD) (Germany), Health Search Database/Thales (HSD) and Emilia Romagna Regional Database (ERD) (Italy), PHARMO Database Network and Integrated Primary Care Information (IPCI) (the Netherlands) and The Health Improvement Network (THIN) (the UK), covering a population of 27 million individuals. The annual prescription rate of APDs was measured overall and for individual medications. APDs were classified as torsadogenic according to the Arizona-CERT list. All analyses were stratified by age, gender and calendar year.nnnRESULTSnA total of 559u2009276 person-years (PYs) of exposure to APDs was captured. The crude annual prescription rate of APD use ranged from 3.0/1000 PYs in ERD to 7.7/1000 PYs in AARHUS. Among APDs with established torsadogenic potential, thioridazine was the most frequently used medication in the UK. Haloperidol was commonly prescribed in Italy and the Netherlands. The use of APDs with torsadogenic potential was much higher in elderly patients.nnnCONCLUSIONSnSubstantial use of APDs with torsadogenic potential has been reported in Europe in recent years, in spite of increasing concerns about their arrhythmogenic potential. This use was even greater in elderly patients, who are at higher risk of SCD.

Appropriateness of Proton Pump Inhibitor (PPI) prescription in patients admitted to hospital: Attitudes of general practitioners and hospital physicians in Italy

INTRODUCTIONnProton pump inhibitor (PPI) prescriptions have raised concern for both huge increase of health expenditure and possible long-term adverse effects.nnnOBJECTIVEnTo evaluate appropriateness of PPI prescription in ambulatory and hospital care.nnnDESIGNnObservational cohort study.nnnPATIENTSnPatients admitted to the Internal Medicine Unit of Bologna S. Orsola Hospital between 15/09/2013 and 15/12/2013. Data on clinical condition and drug therapy were collected at three time points: admission (reflecting GPs prescription), hospital stay and discharge.nnnMAIN MEASURESnAppropriateness of PPI use was evaluated as follows: (1) agreement between PPI use/non-use and appropriate clinical condition; (2) in PPI users, assessment of Medication Appropriateness Index (MAI). Differences in appropriateness among time points were analyzed by chi-square test. Logistic regression model was used to identify possible determinants of PPI appropriateness.nnnKEY RESULTSnAmong 280 patients, 56% received PPI at least once in the three time points. Appropriateness, according to indication of use, was similar between admission and hospital stay (61% vs. 62%; p=0.82) and between hospital stay and discharge (62% vs. 59%; p=0.94). MAI score showed important, although statistically non-significant, change in appropriateness between admission and hospital stay (20% vs. 28%; p=0.16). Age≥65 was always associated with appropriate PPI use (up to OR=4.37; p<0.01), whereas cardiovascular comorbidity and conditions requiring analgesic treatment influenced appropriateness only at admission (OR=3.84; p<0.01 and OR=0.34; p<0.01, respectively).nnnCONCLUSIONSnHospital clinicians only rarely reconsidered GPs choice to prescribe PPI. Room for improvement in PPI appropriateness is represented by (1) assessing gastrointestinal risk in each patient under analgesics and anti-inflammatory drugs, and (2) short-term re-evaluation of PPI prescription after discharge.

Prescribing pattern of antipsychotic drugs during the years 1996-2010

INTRODUCTIONnAntipsychotic drugs (APDs) are used to treat several mental illnesses. Some APDs have long been known to be associated with QT prolongation, potentially leading to torsades de pointes (TdP) and sudden cardiac death (SCD). In 2005, thioridazine was withdrawn because of the risk of SCD, bringing further attention to the arrhythmogenic potential of APDs.nnnAIMnThe aim of the current study was to evaluate the use of APDs in five European countries during the years 1996-2010.nnnMETHODSnA cohort study was conducted using prescription/dispensing data from seven healthcare databases [the AARHUS University Hospital Database (Denmark), the German Pharmacoepidemiological Research Database (GePaRD) (Germany), Health Search Database/Thales (HSD) and Emilia Romagna Regional Database (ERD) (Italy), PHARMO Database Network and Integrated Primary Care Information (IPCI) (the Netherlands) and The Health Improvement Network (THIN) (the UK), covering a population of 27 million individuals. The annual prescription rate of APDs was measured overall and for individual medications. APDs were classified as torsadogenic according to the Arizona-CERT list. All analyses were stratified by age, gender and calendar year.nnnRESULTSnA total of 559u2009276 person-years (PYs) of exposure to APDs was captured. The crude annual prescription rate of APD use ranged from 3.0/1000 PYs in ERD to 7.7/1000 PYs in AARHUS. Among APDs with established torsadogenic potential, thioridazine was the most frequently used medication in the UK. Haloperidol was commonly prescribed in Italy and the Netherlands. The use of APDs with torsadogenic potential was much higher in elderly patients.nnnCONCLUSIONSnSubstantial use of APDs with torsadogenic potential has been reported in Europe in recent years, in spite of increasing concerns about their arrhythmogenic potential. This use was even greater in elderly patients, who are at higher risk of SCD.

Drug-Induced Arrhythmia: Bridging the Gap Between Pathophysiological Knowledge and Clinical Practice

In this issue, Woosley et al. [1] describe an important tool for use in clinical decision making about drugs associated with a risk of Torsades de pointes (TdP), a life-threatening ventricular tachyarrhythmia specifically defined by its characteristic electrocardiographic (ECG) profile. Their work is particularly useful for clinicians and patients because drugs are assigned to categories according to their risk of TdP via the integrated approach, ‘‘Adverse Drug Event Causality Analysis’’ (ADECA). This approach combines updated information from published and unpublished data (mainly disproportionality analysis of major international spontaneous reporting systems). ‘‘CredibleMeds.org’’ is a website through which it is possible to freely (only registration required) view categories of drugs with torsadogenic potential: known TdP risk, possible TdP risk, conditional TdP risk, and drugs to be avoided in patients with long QT syndrome. TdP is a well-described clinical condition, known as a designated medical event in pharmacovigilance. It is typically associated with QT prolongation and can lead to sudden cardiac death (SCD) when it degenerates into ventricular fibrillation [2]. However, as the spectrum of events is seldom observed in its entirety, the diagnosis can only be guessed, not proved, in many cases (e.g., in a patient with SCD a few days after starting a new drug). QT prolongation is relatively common and is a prerequisite for TdP, whereas TdP itself is very rare. The important gap in knowledge relates to how the two are linked. Moreover, drugs such as verapamil can cause QT prolongation with minimal or no observed cases of TdP. Thus, this is a grey area in which a surrogate marker of toxicity (QT prolongation) is extensively documented and largely used by regulators during drug development, but assessing the actual risk of TdP in a single patient is difficult. A tool to assist in clinical decision making is particularly important in areas such as this.

Drug-induced renal injury in neonates: Challenges in clinical practice and perspectives in drug development.

ABSTRACT Introduction: Acute kidney injury (AKI) is frequently diagnosed in the neonatal population, especially in those admitted to intensive care units, and poses several challenges for clinicians mainly because of difficulties in timely identification of renal impairment and the need to administer drugs with potential nephrotoxicity. In this context, research on biomarkers is growing for their implication in the early detection of renal damage and their higher sensitivity in monitoring renal activity, but also as an important tool for drug development. Areas covered: We described the tools currently used to detect renal damage in neonatal settings, their limits and applicability, as well as the role of drugs on renal toxicity occurrence. Subsequently, we discuss current knowledge on new biomarkers for the detection of kidney injury and drug-induced kidney injury in neonates, and the qualification programs developed by regulatory agencies for biomarkers intended as tools in drug development. Expert opinion: Some molecules are emerging as potential biomarkers for early detection of AKI: promising data has demonstrated higher sensitivity and accuracy compared with tools currently used in the clinical setting. In addition, novel techniques (e.g. high power magnetic resonance imaging) to assess long-term consequences of AKI in neonates are in early steps of development.

Adverse pregnancy outcomes in women exposed to gabapentin and pregabalin: data from a population-based study

We undertook a population-based study to assess the comparative risk of spontaneous abortions, terminations of pregnancy (TOPs), major birth defects (MBDs), preterm births and small for gestational age (SGA) infants following intrauterine antiepileptic drug (AED) exposure in the Emilia Romagna region, Northern Italy (4u2009million inhabitants) over a 3-year period (2009–2011). The study was approved by the Local Ethical Committee and authorised by the Hospital Management Executive.nnData were obtained from official regional registries: Certificates of Delivery Assistance (CedAP) for deliveries (>99%u2009coverage of livexa0births and stillbirths) and Hospital Discharge Cards collecting the International Classification of Diseases (ICD) codes of all the discharge diagnoses,xa0for abortionsxa0. AED exposure was based on reimbursed prescription databases as AEDs are supplied and reimbursed by medical prescription in Italy; all drugs registered as AEDs and redeemed with ATC code N03 were considered. MBDs were taken from the Registry of Congenital Malformations (IMER) recording MBDs detected by paediatricians in stillbirths and in live births during the first week of the infant’s life (coveragexa0>95% of births). Each recording from the first three registries contains a unique anonymous code identifying each citizen and linking information among registries. Recordings from the IMER are routinely linked to the CeDAP and consequently to the others, using an additional procedure (correct linkagexa0>98% of the sample). All data were anonymised at the regional source of data to protect patient privacy according to Italian legislation. For the deliveries cohort, the exposure period was based on the date of delivery and gestational age. For the …

Occurrence of Multiple Sclerosis After Drug Exposure: Insights From Evidence Mapping

IntroductionThe role of drugs in the occurrence of multiple sclerosis (MS) is perceived to be insufficiently investigated.ObjectiveThe aim of this study was to map and assess the evidence on MS occurrence after drug exposure, in order to identify possible signals of causal association.MethodsA search strategy was performed in MEDLINE and Embase as of July 2016; references consistent with the aim of the study were analysed to extract relevant measures of causal association between drugs and MS. The Newcastle-Ottawa Scale and appropriate guidelines from the International Society for Pharmacoepidemiology (ISPE) and the International Society of Pharmacovigilance (ISoP) were used to assess the quality of included studies.ResultsAfter screening 832 articles, 58 were selected (of which 14 were found by checking the reference lists of reviews): 30 case reports and case series, 24 longitudinal studies and four randomized controlled trials. Seven longitudinal studies had good (at least 7 out of 9) quality scores, whereas case reports/case series presented several limitations. Half of included articles focused on immunomodulatory drugs (etanercept, infliximab and adalimumab), especially in case reports/series, suggesting an association with MS occurrence. Contraceptives and antibacterials were investigated in some population-based studies, without definite results.ConclusionA heterogeneous pharmacological profile of identified classes emerged. Low strength of evidence and conflicting results highlighted the difficulties in addressing the possible contribution of drugs in MS occurrence. Methodological advances are needed, especially to control the confounding role of underlying disease for specific drug classes.

Pattern of drug use among preterm neonates: results from an Italian neonatal intensive care unit

BackgroundDrug use in preterm neonates admitted to Neonatal Intensive Care Unit (NICU) has been investigated, so far, in terms of unauthorized or off-label use; very little is known on the use of combinations of different active substances, which is frequently required in this population (prophylaxis of infections, treatment of concomitant diseases). The aim of this study was to describe the most common patterns of drug use in an Italian NICU, focusing on those with nephrotoxic potential.MethodsMedical records of preterm neonates (<37xa0weeks of gestational age) weighing less than 1,500xa0g at birth and admitted to an Italian NICU were scrutinized in a 3-year retrospective investigation. Analysis included drug exposure, duration of therapies, co-administration of drugs with potential renal side effects; also daily protein supplement was calculated from parenteral nutrition.ResultsA cohort of 159 preterm neonates was selected; 68 were born weighing less than 1,000xa0g (extremely low birth weight infants, ELBW, Group A), 91 weighed between 1,000 and 1,500xa0g at birth (Group B). Compared to Group B, neonates of Group A were more likely to receive pharmacological treatments: the most used drugs were antibiotics (especially ampicillin and amikacin, pu2009=u2009.07 and pu2009<u2009.001, respectively), antifungals (especially fluconazole, pu2009<u2009.001), and diuretics (especially furosemide, pu2009<u2009.001). Analysis of co-administration of drugs with potential nephrotoxicity showed ampicillin and amikacin as the most reported combination (94.1% of Group A and 31.9% of Group B), the combination of furosemide with antibacterials (ampicillin or amikacin) was also frequently reported, with average period of combination shorter than 2xa0days.ConclusionsELBW infants were exposed to a higher number of drugs compared to other neonates and were more likely to receive associations of drugs with nephrotoxic potential (e.g. furosemide and amikacin), though only for short cycles. Further studies should evaluate the safety profile (especially potential renal side effects) related to most commonly used combinations.