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

a focus on torsadogenic drugs

Alessandro Oteri1,2 PharmD, PhD, Giampiero Mazzaglia3 MD, PhD, Serena Pecchioli3,4 MD, Mariam Molokhia5 MD, Sinna Pilgaard

Ulrichsen6, Lars Pedersen6, Elisabetta Poluzzi7 PharmD, PhD, Fabrizio De Ponti7 MD, PhD, Edeltraut Garbe8 MD, PhD, Tania

Schink8 PhD, Ron Herings11 PharmD, PhD, Irene D. Bezemer11 PharmD, PhD, Miriam CJM Sturkenboom1 PharmD, PhD and

Gianluca Trifirò1,2 MD, PhD.

1Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, Netherlands; 2Department of Clinical and

Experimental Medicine, University of Messina, Messina, Italy; 3Health Search, Italian College of General Practitioners, Florence,

Italy; 4Regional Agency for Healthcare Services of Tuscany, Florence, Italy; 5London School of Hygiene and Tropical Medicine,

London, UK, 6Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark,7Department of Medical and

Surgical Sciences, University of Bologna, Bologna, Italy, 8Leibniz Institute for Epidemiology and Prevention Research - BIPS,

Germany; and,9PHARMO Institute for Drug Outcomes Research, Utrecht, Netherlands.

Correspondence to:

Dr. Gianluca Trifirò

Department of Clinical and Experimental Medicine, University of Messina

Address: Policlinico Universitario G. Martino, Via Consolare Valeria Gazzi, 98125 Messina Italy

Phone: +390902213300

Fax:+390902213264

E-mail: trifirog@unime.it

Running head: Prescribing pattern of antipsychotic drugs in Europe during 1996-2010

Key words: Antipsychotic Drugs, torsadogenic liability, population-based study

Total word count: 2821

Number of tables: 1

Number of figures: 7

What is already known about this subject

Several Antipsychotic drugs (APDs), belonging to both typical and atypical classes, (e.g. sertindole, thioridazine or haloperidol) are

known to be associated with an increased risk of QTc prolongation, potentially leading to serious ventricular arrhythmias (VAs) such

as Torsades de Pointes (TdP) and Sudden Cardiac Death (SCD). In recent years, regulatory authorities from several countries have

expressed concerns about a relationship between APD use and the risk of QTc prolongation, serious VAs and SCD. Consequently,

some APDs have been withdrawn from the market and several others were restricted in their use.

What this study adds

A wide use of APDs with torsadogenic liability was reported in a broad population from five European Countries especially in Italy

and the Netherlands. The safety warnings issued by regulatory agencies contributed to reduce the use of thioridazine in UK and

haloperidol in Italy. The wide use of medications with torsadogenic liability in elderly patients, observed in our study, should be

carefully taken into account given the higher risk of VAs potentially leading to SCD of this population.

Abstract

IntroductionAntipsychotic drugs (APDs) are used to treat several mental illnesses. Some APDs have been known since long 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, raising further attention about the arrhythmogenic potential of APDs.

AimTo evaluate the use of APDs in 5 European Countries during the years 1996-2010.

MethodsA cohort study was conducted using prescription/dispensing data from seven healthcare databases (AARHUS [Denmark], GEPARD [Germany], Health Search/Thales (HSD) and Emilia Romagna Regional Database (ERD) [Italy], PHARMO and IPCI [Netherlands], and THIN [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 by Arizona-CERT list. All analyses were stratified by age, gender, and calendar year.

ResultsA total amount of 559,276 PYs of exposure to APDs was captured. The crude annual prescription rate of APD use ranged from 3.0/1,000 PYs in ERD to 7.7/1,000 PYs in AARHUS. Among APDs with established torsadogenic liability, thioridazine was the most frequently used medication in UK. Haloperidol was commonly prescribed in Italy and the Netherlands. The use of APDs with torsadogenic liability was much higher in elderly patients.

ConclusionsSubstantial use of APDs with torsadogenic liability was reported in the last years in Europe, despite increasing concerns about their arrhythmogenic potential. This use was even greater in elderly patients who are at higher risk of SCD.

Introduction

Antipsychotic drugs (APDs) are the mainstay of the therapy of several mental illnesses such as schizophrenia and other psychoses.

A large use is also reported for the treatment of behavioral symptoms in patients with dementia. In the last decades, an increasing

trend of APD use has been observed worldwide with atypical drugs progressively replacing typical APDs due to a better

extrapyramidal safety profile (1). Several APDs, belonging to both typical and atypical classes, (e.g. sertindole, thioridazine or

haloperidol) are known to be associated with an increased risk of QTc prolongation, potentially leading to serious ventricular

arrhythmias (VAs) such as Torsades de Pointes (TdP) and Sudden Cardiac Death (SCD) (2-4). In recent years, regulatory

authorities from several countries have expressed concerns about a relationship between APD use and the risk of QTc

prolongation, serious VAs and SCD (5-8). Consequently, some APDs have been withdrawn from the market and several others

were restricted in their use. In detail, in 1998, the Committee on Safety of Medicines (CSM) in the United Kingdom (UK) reported 13

cases of VA following use of sertindole. This led to the voluntary withdrawal of the drug from the market, in order to collect

additional evidence (9). In 2001, the drug was reintroduced in Europe under the restriction that treated patients would be enrolled in

a study focusing on mortality to ensure that all patients treated with sertindole were carefully selected and monitored (10). In 2010,

the results of the SCoP study, on the safety of sertindole in relation to all-cause mortality, serious cardiac events including

arrhythmias and cardiac mortality, showed a statistically significant increased risk of cardiac mortality in comparison with

risperidone, further confirming the previous evidence showing an increased cardiac toxicity of this medication (11).

In 1998, thioridazine, mesoridazine and droperidol received a black-box warning from the US Food and Drug Administration (FDA)

regarding the risk of QTc prolongation. By the end of 2000, 21 suspected cases of SCD were reported in patients prescribed

thioridazine which led the CSM to restrict the drug to second-line option for the treatment of schizophrenia under specialist

supervision. Baseline and periodic ECG measurements and monitoring of serum potassium, calcium and magnesium were also

recommended (12). Few months later, droperidol was withdrawn from the market because of its torsadogenic potential and, in

2005, thioridazine was withdrawn from the global market because of the risk of SCD. Finally, in 2007 the FDA released an alert on

the torsadogenic risk of haloperidol especially for high dose and intravenous administration. The FDA recommended periodical

ECG monitoring upon prescription of haloperidol in patients having other QT-prolonging conditions, including electrolyte imbalance,

underlying cardiac abnormalities and hypothyroidism or already treated with other drugs known to prolong the QT interval (13).

More recently, a meta-analysis of observational studies, conducted in the contest of the ARITMO project, showed a variable risk of

VA and SCD between individual APDs in relation to their different ability to block the hERG channel. Medications with higher

potency in blocking the hERG channel (thioridazine, clozapine, risperidone, haloperidol, olanzapine and quetiapine) showed higher

risk of VA and SCD. (14). Conversely, a large study on 18,154 patients with schizophrenia failed to show an association between

ziprasidone and SCD in comparison to olanzapine, despite its known risk of QTc prolongation (15).

Although several studies have analyzed the prescribing pattern of APDs in the general population (16-18), to our knowledge no

previous investigation has evaluated the prescription rate of such medications in relation to their torsadogenic liability in a large

European population. The aims of the present study were: i) to investigate the possible changes in prescribing pattern of APDs in

relation to their torsadogenic liability in 5 European Countries (Denmark, Germany, Italy, Netherlands and UK) during the years

1996-2010 and ii) to evaluate the possible impact of safety warnings and regulatory measures on the use of these medications.

Methods

1. Data sources

Seven healthcare databases have been involved in this study: Health Search Database/CSD Longitudinal Patient (HSD, Italy),

Integrated Primary Care Information (IPCI, the Netherlands), the PHARMO Database Network (the Netherlands), the AARHUS

University Hospital Database (Denmark), The Health Improvement Network (THIN, UK), the German Pharmacoepidemiological

Research Database (GePaRD, Germany) and the Emilia Romagna regional Database (ERD, Italy). All these databases contain

information from the health care records of almost 27 million European citizens. HSD, IPCI and THIN are general practice (GP)

while PHARMO, AARHUS, GEPARD and ERD are comprehensive administrative/record-linkage systems in which drug dispensing

data of a well defined population are linked to a registry of hospital discharge diagnoses and various other registries. Information

collected by these databases includes: inhabitants registry, and drug dispensation/prescription records. Drug

prescriptions/dispensations are coded using the Anatomical Therapeutic Chemical (ATC) classification system in HSD, IPCI,

PHARMO, AARHUS, GEPARD and ERD, or BNF/Multilex classification system in THIN. Table 1 reports the characteristics of each

database as well as the number and percentage of exposed individuals by age groups. For this analysis, databases contributed

data for a period between January 1st, 1996 and December 31st, 2010.

2. Study population

All subjects registered in the databases during the study period, with at least one year of valid records, were included in this

analysis. The total source population included around 27 million individuals from the 5 European countries.

Study drugs

Within the source population, all the persons with at least one prescription/dispensation of APDs (ATC: N05A or corresponding BNF

chapter) during the study period were identified.

On the basis of Arizona-Cert List website (https://www.crediblemeds.org/new-drug-list/, accessed on August 11th, 2015), APDs were

divided into three mutually exclusive groups: i) APDs with established torsadogenic liability (chlorpromazine, droperidol, haloperidol,

mesoridazine, pimozide, sulpiride and thioridazine): when “substantial evidence supports the conclusion that these drugs prolong

the QT interval and are clearly associated with a risk of TdP, even when taken as directed in official labeling ” ii) APDs with possible

torsadogenic liability (aripiprazol, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole and

ziprasidone): when “substantial evidence supports the conclusion that these drugs can cause QT prolongation but there is

insufficient evidence at this time that these drugs, when used as directed in official labeling, are associated with a risk of causing

TdP” and iii) all other APDs (19).

3. Data analysis

For each observation year, annual and monthly prescription rate of APD treatment was evaluated by dividing the number of patients

who received at least one day of exposure to APD in that calendar year or month by the total person-time in that person-year/month

of all subjects alive and registered in the 7 databases on the July, 1st of the same year. The prescription rate of APD use was

expressed as rate per 1,000 Person Years (PYs), with 95% confidence intervals (95% CI). All the analyses were also stratified by

age, database and calendar year. Data transformation was done locally based on standardized common input files and aggregated

data on annual and monthly prescription rate was produced by using Jerboa© v2.9.21, a custom-built software written in Java™

(20). All subsequent analyses on the aggregated data were carried out using SAS v9.2 (Cary, North Carolina) on the central remote

research environment Octopus. A detailed description of these procedures has been published elsewhere (21).

Results

The source population included in the ARITMO study comprised 26,889,720 individuals from 5 European countries (table 1).

Overall, 851,717 patients received at least one prescription/dispensation of APDs during the study period, generating 559,276 PYs

of exposure to APDs.

The crude average prescription rate of APD use ranged between 3.0/1,000 PYs in ERD to 4.1/1,000 PYs in IPCI, 4.3/1,000 PYs in

PHARMO, 4.8/1,000 PYs in THIN, 5.8/1,000 PYs in HSD, 7.0/1,000 PYs in GEPARD and 7.7/1,000 PYs in AARHUS. Figure 1

shows monthly prescription rates, demonstrating constant higher use in Denmark. Stratifying the analysis by age group, an

increasing trend in the overall prescription rate of APD use was reported in over 65 years old persons (figure 2). Drugs with

torsadogenic liability accounted for 54.2% of the total exposure in elderly patients (age ≥ 65 years) (data not shown).

Use by torsadogenic potential

Looking at the distribution of APD use across countries, different volumes of drugs with established and possible torsadogenic

liability, according to the Arizona-CERT list were reported in the seven databases involved in our study: 60.5% in AARHUS

(Denmark), 54.0% in GEPARD (Germany), 47.9% in ERD (Italy), 72.2% in HSD (Italy), 64.9% in PHARMO (the Netherlands),

72.1% in IPCI (the Netherlands) and 52.2% in THIN (UK) (figure 3). Among APD that had undergone regulatory action, only

thioridazine and haloperidol were prescribed in the databases included in our study (figures 4 and 5). Annual prescription rates of

thioridazine use were particularly high in UK, showing an increasing trend of use from 1996 to 2000, followed by a striking fall after

the first warning released by CSM. A similar declining trend in the use of thioridazine until 2005 (year of withdrawal) was reported in

Italy and the Netherlands. Also haloperidol was mostly used in Italy and the Netherlands. However, different trends of use were

observed in these two countries. In Italy, an increasing trend of use was observed until 2007, followed by a decline after an alert

released by the Italian Medicine Agency (AIFA) following the warning on torsadogenic risk of haloperidol that was issued by the

FDA. Conversely, a constant increasing trend was seen in PHARMO and IPCI (the Netherlands). Among drugs with possible

torsadogenic liability, quetiapine and risperidone showed the highest prescription rate, with an increasing trend of use constantly

observed for quetiapine since its marketing in 2000 until the end of the follow-up period (figure 6). Finally, the highest use of

risperidone was seen in Denmark and the Netherlands (figure 7).

Discussion

This population-based study evaluated the prescribing pattern of APDs in 5 European countries in relation to their perceived

torsadogenic liability as per Arizona-CERT list and before and after safety warnings on the risk of QTc prolongation for thioridazine

and haloperidol. The use was highest in Denmark and lowest in the Netherlands and Italy with a rather constant prescription rate

observed during the whole study period. The prescribing pattern of APD use in the general population was evaluated in several

previous investigations. In their analysis, Kaye et al. observed an increasing use of APDs in UK during the years 1991-2000 (22).

This finding is consistent with our data showing a similar trend during the overlapping periods in THIN database (UK). Another

study, carried out in Italy, found a rather stable prevalence of use during the years 1999-2002 (18),which is also comparable with

our investigation showing a steady use of APDs in Italy during the same time window. Furthermore, the higher prescription rate of

APDs observed in PHARMO as compared to IPCI might be explained by the fact that the additional dispensings in PHARMO are

from specialist prescriptions. Analyzing the distribution of APD use based on their torsadogenic liability, higher volumes of drugs

with established and possible torsadogenic liability were reported in Italy and the Netherlands with more than 70% of the total

amount of exposure observed in HSD and PHARMO. Such evidence is in line with a recent investigation, also produced in the

contest of the ARITMO project, showing a higher exposure to APDs with very strong torsadogenic signals based on

pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS) across Europe (23,24). Among drugs with

established torsadogenic liability, only use of thioridazine and haloperidol was reported in our study. Thioridazine was the most

frequently prescribed medication in UK during the period 1996-2000, followed by a striking decline in concomitance with the first

alert released by the CSM in 2000 (11). The increasing trend of thioridazine use observed in THIN is consistent with the above

mentioned UK study, reporting this drug as the most commonly prescribed APD in UK during the years 1991-2000 (22). Although

less representative, a similar reduction in the use of thioridazine was reported in databases with longer follow-up such as HSD,

PHARMO and IPCI. This is also in line with another study carried out in Australia, showing 80% fall in thioridazine use from 1995 to

2001 (25).

Concerning haloperidol, higher prescription rate was reported in Italy and the Netherlands. However, different trends of use were

observed in databases from these two countries. An increasing use of haloperidol was reported in HSD (Italy) until 2007, followed

by a reduction probably due to the introduction by the AIFA of a warning on the risk of serious VAs and SCD, especially when the

drug is administered intravenously or in high doses (25). A similar declining trend was also seen in ERD during the same time

period (please, see below for a correct interpretation of ERD values). Based on this warning, the AIFA changed the Summary of

Product Characteristics, recommending baseline and periodical ECG monitoring in patients at high cardiovascular risk (26).

Conversely, an increasing trend of haloperidol use was observed in PHARMO and IPCI during the entire study period. The effect of

safety warnings on APD use was further investigated in previous studies (27,28). A recent US study showed a reduction in the use

of atypical APDs as consequence of a FDA warning linking atypical APDs to an increased risk of all-cause mortality in elderly

patients affected by dementia (27). A similar falling trend was seen in another study evaluating the prescribing pattern of atypical

APDs in an Italian setting of elderly demented patients (28). A recent Spanish investigation, analysed the changing pattern of use of

atypical APDs (olanzapine and risperidone) by means of interrupted time series analysis, after the introduction of specific regulatory

measures concerning such medications. The study showed a reduction in the prescribing pattern of risperidone after the

introduction of a safety warning toward the drug (29). Likewise, in our study the use of APDs in Europe seemed to be highly

influenced by safety warnings and health regulatory measures on QTc prolongation and severe VAs, potentially leading to SCD.

This finding confirms the importance of health regulatory measures in influencing the use of APDs in the general population.

Among drugs with possible torsadogenic liability, quetiapine and risperidone showed the highest use. An increasing trend in the

prescription rate was constantly reported for quetiapine since its marketing in 2000 until the end of the follow-up period. On one

hand, this result might be due to the tendency of new drugs to be widely prescribed soon after their marketing (30,31) but, on the

other hand, it may also reflects the increasing trend of atypical APD use in the general population because of their better

extrapyramidal safety profile (1). This observation could also explain the increasing trend in the use of risperidone observed mainly

in Denmark and the Netherlands. The increasing prescription rate APDs with advancing age reported in our study is also consistent

with several previous investigations showing higher use of APDs in elderly patients (18). Such trend may be explained by the high

use of APDs for the treatment of behavioral and psychological symptoms in elderly demented patients, which was already

documented in previous investigations (27,28).

Notably, drugs with torsadogenic liability accounted for 54.2% of the total PYs of exposure in the elderly population. Since previous

evidence showed an increasing risk of VAs and SCD in elderly patients treated with APDs, especially those with dementia (32,33),

a more cautious use of drugs with torsadogenic liability would have been expected in this higher risk group as compared to younger

patients in our study.

Limitations of the study

The results of our study should be considered in view of some limitations. First of all, we used outpatient prescription/dispensation

data and had no information about actual use of the medications. Second, the study was performed using computerized medical

records from 7 healthcare databases thus limiting the generalizability of the results, since some categories of patients, such as

inpatients or elderly persons with mental illnesses residing in nursing homes, were missing. Furthermore, the very low prescription

rate of atypical APDs observed in ERD may be explained by the fact that in Italy these drugs are partially dispensed through direct

distribution from local psychiatric services and cannot be captured in the outpatient pharmaceutical dispensing flow which was

considered in this study. As a consequence, an underestimation of the use of atypical APDs may have been occurred in this

database. Nevertheless, because GPs in Italy initiate APD treatment for some patients and continue treatments begun by

specialists for other patients, data from HSD are likely to be more representative of national trends than those from ERD, especially

for atypical APDs.

Conclusions

In conclusion, a large use of APDs with torsadogenic liability was reported in the last years in the 5 European countries, despite

increasing concerns about their arrhythmogenic potential. The safety warnings issued by regulatory agencies contributed to reduce

the use of thioridazine in UK and haloperidol in Italy. The wide use of these medications in elderly patients should be carefully taken

into account, given the higher risk of VAs potentially leading to SCD of this population.

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Tables and figures

Table. Characteristics of healthcare databases involved in the ARITMO project

Figure1. Monthly prescription rate (x1,000PYs) of APD use per calendar time and database during the observed years

Figure 2. Overall prescription rate (x1,000PYs) of APD use per age and database during the observed years

Figure 3.Distribution of APD use across different countries (% of total amount of exposure)

Figure 4. Annual prescription rate (x1,000PYs) of APD subjected to regulatory action: Thioridazine

Figure 5.Annual prescription rate (x1,000PYs) of APD subjected to regulatory action: Haloperidol

Figure 6.Annual prescription rate (x1,000PYs) of APD use with possible torsadogenic liability: Quetiapine

Figure 7.Annual prescription rate (x1,000 PYs) of APD use with possible torsadogenic liability: Risperidone

Acknowledgements

Funding: The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 241679 – the ARITMO project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

DisclosureEdeltraut Garbe is running a department that occasionally performs studies for pharmaceutical industries. The companies include Mundipharma, Bayer-Schering, Stada, Sanofi-Aventis, Sanofi-Pasteur, Novartis, Celgene and GSK. EG has been consultant to Bayer-Schering, Nycomed, Teva and Novartis in the past.Miriam Sturkenboom is running a group that occasionally performs studies for pharmaceutical industries with the full freedom to publish. The companies include Pfizer, EliLilly, AstraZeneca.

Author Contributions

Conceived and designed the experiments: AO, GM, MCJMS and GT

Collected and analysed the data: AO, SP, SPU, EP, TS and IDB

Wrote the manuscript: AO, GT

Made substantive suggestions for data interpretation, contributed to the discussion: MM, LP, FDP, EG and RH

Revised and approved the final submitted manuscript: all the authors