Janet Sultana

Clinical and economic burden of adverse drug reactions

Adverse drug reactions (ADRs) are unwanted drug effects that have considerable economic as well as clinical costs as they often lead to hospital admission, prolongation of hospital stay and emergency department visits. Randomized controlled trials (RCTs) are the main premarketing methods used to detect and quantify ADRs but these have several limitations, such as limited study sample size and limited heterogeneity due to the exclusion of the frailest patients. In addition, ADRs due to inappropriate medication use occur often in the real world of clinical practice but not in RCTs. Postmarketing drug safety monitoring through pharmacovigilance activities, including mining of spontaneous reporting and carrying out observational prospective cohort or retrospective database studies, allow longer follow-up periods of patients with a much wider range of characteristics, providing valuable means for ADR detection, quantification and where possible reduction, reducing healthcare costs in the process. Overall, pharmacovigilance is aimed at identifying drug safety signals as early as possible, thus minimizing potential clinical and economic consequences of ADRs. The goal of this review is to explore the epidemiology and the costs of ADRs in routine care.

Antipsychotic use in elderly patients and the risk of pneumonia

Antipsychotics are frequently and increasingly prescribed off-label for the treatment of behavioral and psychological symptoms associated with dementia, despite their modest efficacy. Instead, the safety profile of antipsychotics has been questioned repeatedly in recent years with various concerns, including death. Meta-analyses of randomized controlled trials found that one of the major causes of death associated with atypical antipsychotics use was pneumonia. Only few observational studies, however, have investigated the risk of pneumonia in elderly patients, especially among those receiving conventional antipsychotics. The aim of this editorial is to synthesize the current evidence from observational studies regarding the risk of pneumonia in elderly patients receiving either conventional or atypical antipsychotics. The studies conducted so far document that the risk of pneumonia is two- to threefold increased in a dose-dependent fashion with both classes compared to nonuse, with a possibly higher risk attributable to atypical antipsychotics. The risk seems to peak at the beginning of treatment (e.g., 7 – 30 days), and dissipates over time for both conventional and atypical antipsychotics. The risk–benefit ratio suggests that there will be 1 excess hospitalization for pneumonia for every 2 – 5 patients receiving any clinical improvement in symptoms. Considering the modest improvement in terms of efficacy, the risks associated with antipsychotics in elderly patients may outweigh their benefit.

Association of Individual Non-Steroidal Anti-Inflammatory Drugs and Chronic Kidney Disease: A Population-Based Case Control Study

Background Non-steroidal anti-inflammatory agents (NSAIDs) are known to be associated with renal damage. No clear evidence exists regarding differential risk of chronic kidney disease (CKD), specifically, across various NSAIDs. Aim The aim of this population-based case-control study was to evaluate the association between use of individual NSAIDs and risk of CKD in a general population of Southern Italy. Methods A nested case-control study was carried out using the general practice Arianna database, identifying incident CKD patients as cases and matched controls from 2006 to 2011. The date of first CKD diagnosis was defined as the index date (ID). Conditional logistic regressions were performed to estimate the risk of CKD associated with NSAIDs by class and individual drugs as compared to non-use during different time windows (within one year, six or three months prior to ID), with the latter being defined as current users. Among current users, the effect of cumulative exposure to these drugs was evaluated. Results Overall, 1,989 CKD cases and 7,906 matched controls were identified. A statistically significant increase in the risk of CKD was found for current users of oxicams (adjusted OR: 1.68; 95% CI: 1.15-2.44) and concerning individual compounds, for ketorolac (adj. OR: 2.54; 95% CI: 1.45-4.44), meloxicam (adj. OR: 1.98; 95% CI: 1.01-3.87) and piroxicam (adj. OR: 1.95; 95% CI: 1.19-3.21). Conclusions The risk of CKD varies across individual NSAIDs. Increased risk has been found for ketorolac, which may precipitate subclinical CKD through acute renal damage, and long-term exposure to oxicams, especially meloxicam and piroxicam.

Indications of newer and older anti-epileptic drug use: findings from a southern Italian general practice setting from 2005–2011

AIMS The aim of the study was to analyze the prescribing pattern of both newer and older AEDs. METHODS A population of almost 150 000 individuals registered with 123 general practitioners was included in this study. Patients who received at least one AED prescription over 2005-2011 were identified. The 1 year prevalence and cumulative incidence of AED use, by drug class and individual drug, were calculated over the study period. Potential predictors of starting therapy with newer AEDs were also investigated. RESULTS The prevalence of use per 1000 inhabitants of older AEDs increased from 10.7 (95% CI10.1, 11.2) in 2005 to 13.0 (95% CI12.4, 13.6) in 2011, while the incidence remained stable. Newer AED incidence decreased from 9.4 (95% CI 8.9, 9.9) in 2005 to 7.0 (95% CI 6.6, 7.5) in 2011, with a peak of 15.5 (95% CI 14.8, 16.1) in 2006. Phenobarbital and valproic acid were the most commonly prescribed AEDs as starting therapy for epilepsy. Gabapentin and pregabalin accounted for most new pain-related prescriptions, while valproic acid and lamotrigine were increasingly used for mood disorders. Female gender (OR 1.36, 95% CI 1.20, 1.53), age ranging between 45-54 years (OR 1.39, 95% CI 1.16, 1.66) and pain as an indication (OR 16.7, 95% CI, 13.1, 21.2) were associated with newer AEDs starting therapy. CONCLUSIONS Older AEDs were mainly used for epileptic and mood disorders, while newer drugs were preferred for neuropathic pain. Gender, age, indication of use and year of starting therapy influenced the choice of AED type. The decrease of newer AED use during 2007 is probably related to the restricted reimbursement criteria for gabapentin and pregabalin.

The Burden of Nephrotoxic Drug Prescriptions in Patients with Chronic Kidney Disease: A Retrospective Population-Based Study in Southern Italy

Background The use of nephrotoxic drugs can further worsening renal function in chronic kidney disease (CKD) patients. It is therefore imperative to explore prescribing practices that can negatively affect CKD patients. Aim To analyze the use of nephrotoxic drugs in CKD patients in a general population of Southern Italy during the years 2006–2011. Methods The general practice “Arianna” database contains data from 158,510 persons, registered with 123 general practitioners (GPs) of Caserta. CKD patients were identified searching: CKD-related ICD-9 CM codes among causes of hospitalization; CKD-relevant procedures undergone in hospital (e.g. dialysis); drug prescriptions issued for a CKD-related indication. A list of nephrotoxic drugs was compiled and validated by pharmacologists and nephrologists. The summary of product characteristics was used to classify drugs as ‘contraindicated’ or ‘to be used with caution’ in renal diseases. Frequency of nephrotoxic drug use, overall, by drug class and single compounds, by GPs within one year prior or after first CKD diagnosis and within one year after dialysis entry was calculated. Results Overall, 1,989 CKD patients and 112 dialysed patients were identified. Among CKD patients, 49.8% and 45.2% received at least one prescription for a contraindicated nephrotoxic drug within one year prior or after first CKD diagnosis, respectively. In detail, 1,119 CKD patients (56.3%) had at least one nonsteroidal anti-inflammatory drugs (NSAIDs) prescription between CKD diagnosis and end of follow-up. A large proportion of CKD patients (35.6%) were treated with NSAIDs for periods exceeding 90 days. Contraindicated nephrotoxic drugs were used commonly in CKD, with nimesulide (16.6%) and diclofenac (11.0%) being most frequently used. Conclusions Contraindicated nephrotoxic drugs were highly prescribed in CKD patients from a general population of Southern Italy. CKD diagnosis did not seem to reduce significantly the prescription of nephrotoxic drugs, which may increase the risk of preventable renal function deterioration.

Antidepressant use in the elderly: the role of pharmacodynamics and pharmacokinetics in drug safety.

Introduction: Antidepressants (ADs) are widely used among elderly persons, making AD-related safety an important issue. Areas covered: This review highlights safety considerations related to AD use including risks associated with inappropriate and off-label use. The age-related pharmacokinetic and pharmacodynamic changes underlying safety concerns connected to ADs are outlined. Drug–drug interactions as a cause of AD-related adverse drug reactions (ADRs) are also discussed. We reviewed scientific evidence concerning three important safety outcomes related to ADs in elderly persons: cardiac arrhythmias, hyponatraemia and falls/fractures. Expert opinion: Several AD-related ADRs in elderly people are likely to be preventable. Current evidence suggests that selective serotonin re-uptake inhibitors (SSRIs) are best avoided particularly in persons with kidney disease due to the risk of hyponatraemia. The use of tricyclic antidepressants (TCAs) should be limited in the elderly due to anticholinergic adverse effects. TCAs should also be avoided in elderly persons at high risk of cardiovascular events due to a risk of cardiac arrhythmia. Emerging evidence suggests that SSRIs also have arrhythmogenic potential. Both TCAs and SSRIs should be used cautiously in elderly persons at risk of falls. Future research in this area should aim to investigate the lowest effective dose of AD possible, the relationship between AD dose and adverse effects, and which elderly subgroups are most prone to develop severe ADRs.

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.

Chronic Kidney Disease Requiring Healthcare Services: A New Approach to Evaluate Epidemiology of Renal Disease

Background. Screening-based CKD estimates may not provide a sufficient insight into the impact of CKD on the use of healthcare resources in clinical practice. The aim of this study was to evaluate the epidemiology of “medicalized” CKD, that is, CKD requiring healthcare services, in an outpatient setting. Design, Setting, Participants, and Measurements. This is a retrospective, longitudinal population-based study conducted in a large general practice setting in Southern Italy (Caserta) using a healthcare database. Over 2006–2011, all patients with a CKD diagnosis, either through CKD-related indications of use associated with drug prescriptions or through CKD-related hospital discharge diagnoses/procedures, were identified using this database. The prevalence of “medicalized” CKD in the general population of Caserta was estimated by age, gender, and calendar year. Results. Overall, 1,989 (1.3%) patients with a diagnosis of CKD were identified from 2006–2011 in the Caserta general population. The one year prevalence increased from 0.9% in 2006 to 1.6% in 2011, which is much lower compared to previous screening-based studies. The prevalence was slightly higher in males and increased significantly with advancing age (in 2011, 0.2% in ≤44 years old versus 9.2% in >80 years old). Conclusions. The findings of this study suggest that, in the general population, the prevalence of “medicalized” CKD is lower compared to the screening-based CKD prevalence.

From Big Data to Smart Data for Pharmacovigilance: The Role of Healthcare Databases and Other Emerging Sources

In the last decade ‘big data’ has become a buzzword used in several industrial sectors, including but not limited to telephony, finance and healthcare. Despite its popularity, it is not always clear what big data refers to exactly. Big data has become a very popular topic in healthcare, where the term primarily refers to the vast and growing volumes of computerized medical information available in the form of electronic health records, administrative or health claims data, disease and drug monitoring registries and so on. This kind of data is generally collected routinely during administrative processes and clinical practice by different healthcare professionals: from doctors recording their patients’ medical history, drug prescriptions or medical claims to pharmacists registering dispensed prescriptions. For a long time, this data accumulated without its value being fully recognized and leveraged. Today big data has an important place in healthcare, including in pharmacovigilance. The expanding role of big data in pharmacovigilance includes signal detection, substantiation and validation of drug or vaccine safety signals, and increasingly new sources of information such as social media are also being considered. The aim of the present paper is to discuss the uses of big data for drug safety post-marketing assessment.

Treatment of Medication-Related Osteonecrosis of the Jaw and its Impact on a Patient’s Quality of Life: A Single-Center, 10-Year Experience from Southern Italy

IntroductionNo official guidelines are available for the management of medication-related osteonecrosis of the jaw (MR-ONJ). The additional benefit of surgery after pharmacological treatment is debated by both clinicians and patients.ObjectiveThe aim of this study was to evaluate the changes in patients’ MR-ONJ-related quality of life (QoL) after pharmacological treatment with or without surgery in a large cohort affected by MR-ONJ.MethodsAnonymized data on patients diagnosed with MR-ONJ were extracted from the database of the Osteonecrosis of the Jaw Treatment Center (University of Messina, Italy) in the years 2005–2015. QoL was evaluated at the moment of MR-ONJ diagnoses (T0), after pharmacological treatment with or without surgery (T1 and T2, respectively), based on scores from the European Organisation for Research and Treatment of Cancer (EORTC) QOL Module for Head and Neck Cancer (global oral health status [GOHS]) and a visual analog scale (VAS), stratified by indication for use.ResultsAmong 100 patients, 36% were affected by osteoporosis (OSTEO group) and 64% were affected by cancer (ONC group). Considering T0, QoL scores were higher in the OSTEO group then in the ONC group. At T1, GOHS and VAS increased in both groups (OSTEO group: +9.9% and +39.9%; ONC group: +35.4 and +97.2%, respectively). Pharmacological treatment was effective in reducing pain (OSTEO group: −22.0%; ONC group: −44.8%), and social contact troubles (OSTEO group: −40.3%; ONC group: −26.7%). At T2, GOHS and VAS further increased. Scores related to ‘pain’ and the troubles related to the ‘social dimension’ also decreased (OSTEO group: −91.3% and −72.0%; ONC group: 50.8% and −16.4%, respectively).ConclusionsMR-ONJ-related QoL increased after pharmacological treatment and, more notably, after surgery, which may offer benefits to selected patients. QoL data may help clinicians in promoting tailored management of MR-ONJ.