Gianluca Trifirò

Combining electronic healthcare databases in Europe to allow for large-scale drug safety monitoring: the EU-ADR Project

In this proof‐of‐concept paper we describe the framework, process, and preliminary results of combining data from European electronic healthcare record (EHR) databases for large‐scale monitoring of drug safety.

Patterns of persistence with antihypertensive medications in newly diagnosed hypertensive patients in Italy: a retrospective cohort study in primary care.

Objective To describe patterns of persistence and related primary care costs associated with first antihypertensive treatment. Design and setting Retrospective cohort study during 2000–2001, using information from 320 Italian general practitioners. Participants We studied 13 303 patients with newly diagnosed hypertension, who received a first single antihypertensive prescription within 3 months after diagnosis. Main outcome measures Persistence with first-line single treatment, categorized as follows: continuers: patients continuing the first-line medication for at least 1 year; combiners: patients receiving an additional antihypertensive drug and continuing the initial medication; switchers: patients changing from the first-line to another class of antihypertensive drug and discontinuing the initial treatment; discontinuers: patients stopping the first-line treatment without having another prescription until the end of the follow-up. Primary care costs were expressed as the cost of hypertension management per person-year of follow-up. Results In the study cohort, 19.8% were continuers, 22.1% were combiners, 15.4% were switchers, and 42.6% were discontinuers. Continuation was greatest with angiotensin II type 1 receptor blocking agents (25.2%), calcium channel blockers (23.9%) and angiotensin-converting enzyme inhibitors (23.3%). Severe hypertension [hazards ratio 1.30; 95% confidence interval (CI) 1.18 to 1.43] and severe health status (hazards ratio 1.22; 95% CI 1.15 to 1.30) increased the risk of discontinuation. The likelihood of needing an additional antihypertensive drug was associated with mild-to-severe baseline blood pressure, diabetes (hazards ratio 1.20; 95% CI 1.06 to 1.36), and familial history of cardiovascular disease (hazards ratio 1.24; 95% CI 1.10 to 1.39). Discontinuers accounted for 22.4% of the total primary care cost. Initial treatment with angiotensin II type 1 receptor blocking agents and β-blockers resulted in incremental primary care costs of &U20AC;145.2 and &U20AC;144.2, respectively, compared with diuretics. Combiners and switchers increased the primary care cost by &U20AC;140.1 and &U20AC;11.7, compared with continuers. Conclusion Persistence with first-line single antihypertensive drugs is extremely low during the first year of treatment. Potential cost saving should be possible by reducing the high frequency of discontinuation. Diuretics represent the least expensive therapeutic option, although further investigations in the long-term are needed to analyse the effects of persistence on therapeutic effectiveness and related costs.

Data mining on electronic health record databases for signal detection in pharmacovigilance: which events to monitor?

Data mining on electronic health records (EHRs) has emerged as a promising complementary method for post‐marketing drug safety surveillance. The EU‐ADR project, funded by the European Commission, is developing techniques that allow mining of EHRs for adverse drug events across different countries in Europe. Since mining on all possible events was considered to unduly increase the number of spurious signals, we wanted to create a ranked list of high‐priority events.

Epidemiology of gout and hyperuricaemia in Italy during the years 2005–2009: a nationwide population-based study

Objective To assess the epidemiology of gout and hyperuricaemia in the Italian general population during the years 2005–2009. Methods Using the Italian primary care database (Health Search/CSD Longitudinal Patient Database), the prevalence, incidence and recurrence rates of gout and/or hyperuricaemia (serum urate level >360 mmol/l (6 mg/dl)) in outpatients aged ≥18 years during the years 2005–2009 were estimated. Rates together with 95% CI were measured overall and stratified by age, gender and calendar year. The characteristics of patients with newly diagnosed gout and hyperuricaemia were investigated and compared with the general population. Results The prevalence of gout increased from 6.7 per 1000 inhabitants in 2005 to 9.1 per 1000 inhabitants in 2009. It increased with advancing age and was fourfold higher in men. A similar trend was observed for asymptomatic hyperuricaemia (85.4 per 1000 inhabitants in 2005 vs 119.3 per 1000 inhabitants in 2009). The incidence of gout remained stable during the observation years (0.93 per 1000 person years in 2005 vs 0.95 in 2009). Recurrent episode rate was 19.1% during the first year following the first gout attack and 31.6% during the following 5 years. Advanced age, increased levels of uric acid, nephrolithiasis and concomitant use of ciclosporin were the main predictors of recurrence of gout attacks. Conclusion The prevalence of gout and hyperuricaemia increased in Italy from 2005 to 2009. A high recurrence rate for gout attack was observed during the first year following the first episode. Early management of hyperuricaemia in patients at higher risk of recurrent gout attack should be considered in primary care.

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.

Association of Community-Acquired Pneumonia With Antipsychotic Drug Use in Elderly Patients: A Nested Case–Control Study

BACKGROUND According to safety alerts from the U.S. Food and Drug Administration, pneumonia is one of the most frequently reported causes of death in elderly patients with dementia who are treated with antipsychotic drugs. However, epidemiologic evidence of the association between antipsychotic drug use and pneumonia is limited. OBJECTIVE To evaluate whether typical or atypical antipsychotic use is associated with fatal or nonfatal pneumonia in elderly persons. DESIGN Population-based, nested case-control study. SETTING Dutch Integrated Primary Care Information database. PATIENTS Cohort of persons who used an antipsychotic drug, were 65 years or older, and were registered in the IPCI database from 1996 to 2006. Case patients were all persons with incident community-acquired pneumonia. Up to 20 control participants were matched to each case patient on the basis of age, sex, and date of onset. MEASUREMENTS Risk for fatal or nonfatal community-acquired pneumonia with atypical and typical antipsychotic use. Antipsychotic exposure was categorized by type, timing, and daily dose, and the association with pneumonia was assessed by using conditional logistic regression. RESULTS 258 case patients with incident pneumonia were matched to 1686 control participants. Sixty-five (25%) of the case patients died in 30 days, and their disease was considered fatal. Current use of either atypical (odds ratio [OR], 2.61 [95% CI, 1.48 to 4.61]) or typical (OR, 1.76 [CI, 1.22 to 2.53]) antipsychotic drugs was associated with a dose-dependent increase in the risk for pneumonia compared with past use of antipsychotic drugs. Only atypical antipsychotic drugs were associated with an increase in the risk for fatal pneumonia (OR, 5.97 [CI, 1.49 to 23.98]). LIMITATIONS Antipsychotic exposure was based on prescription files. Residual confounding due to unmeasured covariates or severity of disease was possible. CONCLUSION The use of either atypical or typical antipsychotic drugs in elderly patients is associated in a dose-dependent manner with risk for community-acquired pneumonia.

Prescribing patterns of antiepileptic drugs in Italy : a nationwide population-based study in the years 2000-2005

To evaluate prevalence of use and prescribing patterns of antiepileptic drugs (AEDs) in Italian general practice. Primary care data were obtained from the Health Search Database, a longitudinal observational database implemented by the Italian College of General Practitioners (GPs). We selected 465 061 subjects registered by the end of 2005 in the lists of 320 GPs, homogeneously distributed throughout Italy. Prevalence of AED use was assessed in the entire sample and by drug type, age group, year and main geographic area (north, centre and south/islands). Overall, 24 383 subjects (5.2%) received at least one AED prescription in the study period. Prevalence of AED use (with 95% confidence interval) increased progressively from 7.1 (6.9–7.3) in 2000 to 11.8 (11.5–12.1) in 2005 for old AEDs and from 1.1 (1.0–1.2) to 12.2 (11.9–12.5) for new AEDs. Carbamazepine, phenobarbital and valproic acid were the most common AEDs until 2003, when gabapentin became first. There were no differences in prescribing patterns in the three main geographic areas. Newer AEDs were mostly used in patients aged 65 years and older. The more widespread use of newer AEDs was for mood disorders or pain. Older AED currently remain first line drugs for epileptic disorders. An increasing use of AEDs has been recently observed over a 6‐year period in Italian general practice, mostly explained by newer compounds used for conditions other than epilepsy.

Clinically Significant Drug Interactions with Newer Antidepressants

After the introduction of selective serotonin reuptake inhibitors (SSRIs), other newer antidepressants with different mechanisms of action have been introduced in clinical practice. Because antidepressants are commonly prescribed in combination with other medications used to treat co-morbid psychiatric or somatic disorders, they are likely to be involved in clinically significant drug interactions. This review examines the drug interaction profiles of the following newer antidepressants: escitalopram, venlafaxine, desvenlafaxine, duloxetine, milnacipran, mirtazapine, reboxetine, bupropion, agomelatine and vilazodone.In general, by virtue of a more selective mechanism of action and receptor profile, newer antidepressants carry a relatively low risk for pharmacodynamic drug interactions, at least as compared with first-generation antidepressants, i.e. monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). On the other hand, they are susceptible to pharmacokinetic drug interactions. All new antidepressants are extensively metabolized in the liver by cytochrome P450 (CYP) isoenzymes, and therefore may be the target of metabolically based drug interactions. Concomitant administration of inhibitors or inducers of the CYP isoenzymes involved in the biotransformation of specific antidepressants may cause changes in their plasma concentrations. However, due to their relatively wide margin of safety, the consequences of such kinetic modifications are usually not clinically relevant. Conversely, some newer antidepressants may cause pharmacokinetic interactions through their ability to inhibit specific CYPs. With regard to this, duloxetine and bupropion are moderate inhibitors of CYP2D6. Therefore, potentially harmful drug interactions may occur when they are coadministered with substrates of these isoforms, especially compounds with a narrow therapeutic index. The other new antidepressants are only weak inhibitors or are not inhibitors of CYP isoforms at usual therapeutic concentrations and are not expected to affect the disposition of concomitantly administered medications.Although drug interactions with newer antidepressants are potentially, but rarely, clinically significant, the use of antidepressants with a more favourable drug interaction profile is advisable. Knowledge of the interaction potential of individual antidepressants is essential for safe prescribing and may help clinicians to predict and eventually avoid certain drug combinations.

Age-related Changes in Pharmacodynamics: Focus on Drugs Acting on Central Nervous and Cardiovascular Systems

Aging is characterized by progressive impairment of functional capacities of all system organs, reduction in homeostatic mechanisms, and altered response to receptor stimulation. These age-related physiologic changes influence both pharmacokinetics and pharmacodynamics of drugs in elderly patients. Pharmacokinetic and pharmacodynamics changes as well as polypharmacy and comorbidities may alter significantly the effect of pharmacological treatment with advancing age. With the same drug concentration at the site of action, significant differences in the response to several drugs have been observed in older patients as compared to younger patients. Elderly patients are particularly suceptibles to the effects of frequently prescribed drugs acting on central nervous system, such as benzodiazepines, antidepressants, antipsychotics and lithium, with high potential for adverse drug reactions. Moreover, in older patients increased sensitivity to warfarin resulting in increased risk of bleeding has been previously documented. On the other hand, reduced effectiveness of conventional doses of cardiovascular drugs, such as diuretics and β-blockers, has been observed. Due to pharmacodynamic changes, therefore, dose adjustment of the above mentioned cardiovascular and psychotropic drugs is recommended in elderly. Clinicians should be aware of the age-related physiologic changes affecting several organ systems and their implications on the effect of drugs that are commonly prescribed to elderly patients.

Use of antipsychotics in elderly patients with dementia: Do atypical and conventional agents have a similar safety profile?

Pharmacological treatment of dementia addresses two main clinical features of the disease: cognitive deterioration with predominantly memory loss and behavioural and psychological symptoms (BPSD). While cholinesterase inhibitors are recommended in an attempt to delay memory loss and disability, what should be considered the most appropriate pharmacological treatment for BPSD has remained questionable. Antipsychotic medications, conventional and atypical agents, have been increasingly utilized in clinical practice but only a small number of clinical studies have investigated their relative cost-benefit ratio. This review focuses on the safety of atypical and conventional antipsychotics when used in patients with BPSD. Overall, atypical and conventional antipsychotics are associated with a similarly increased risk for all-cause mortality and cerebrovascular events. Relative to atypical agents users, patients being treated with conventional antipsychotics have an increased incidence of cardiac arrhythmias and extrapyramidal symptoms. Conversely, users of atypical antipsychotics are exposed to an increased risk of venous thromboembolism and aspiration pneumonia. Also, metabolic effects (i.e. increased risk of diabetes, weight gain) have consistently been documented in clinical studies with atypical antipsychotics, although this effect tends to be attenuated with advancing age and in elderly patients with dementia. Antipsychotics, both conventional and atypical, should be used with caution only when nonpharmacologic approaches have failed to adequately control BPSD. More effective interventions are necessary to improve postmarket drug safety in vulnerable populations.