Antipsychotic drug exposure and risk of pulmonary embolism: a population-based, nested case–control study

Conti et al. BMC Psychiatry Antipsychotic drug exposure and risk of pulmonary embolism: a population-based, nested case-control study Valentino Conti 3 Mauro Venegoni 3 Alfredo Cocci 3 Ida Fortino 2 Antonio Lora 1 Corrado Barbui 0 0 WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona , Verona , Italy 1 Department of Mental Health , Lecco , Italy 2 Unit of Community Health Services, Regional Health Ministry, Lombardy Region , Milan , Italy 3 Regional Centre for Pharmacovigilance, Lombardy Region , Milano , Italy Background: Only three observational studies investigated whether exposure to antipsychotics is associated with an increased risk of pulmonary embolism, with conflicting results. This study was therefore carried out to establish the risk of pulmonary embolism associated with antipsychotic drugs, and to ascertain the risk associated with first- and second-generation antipsychotic drugs, and with exposure to individual drugs. Methods: We identified 84,253 adult individuals who began antipsychotic treatment in a large Italian health care system. Cases were all cohort members who were hospitalized for non-fatal or fatal pulmonary embolism during follow-up. Up to 20 controls for each case were extracted from the study cohort using incidence density sampling and matched by age at cohort entry and gender. Each individual was classified as current, recent or past antipsychotic user. The occurrence non-fatal or fatal pulmonary embolism was the outcome of interest. Results: Compared to past use, current antipsychotic use more than double the risk of pulmonary embolism (odds ratio 2.31, 95% confidence interval 1.16 to 4.59), while recent use did not increase the risk. Both conventional and atypical antipsychotic exposure was associated with an increase in risk, and the concomitant use of both classes increased the risk of four times (odds ratio 4.21, 95% confidence interval 1.53 to 11.59). Conclusions: Adding the results of this case-control study to a recent meta-analysis of three observational studies substantially changed the overall estimate, which now indicates that antipsychotic exposure significantly increases the risk of pulmonary embolism. - Background Pulmonary embolism (PE) is a significant cause of morbidity and mortality, occurring at an estimated 95 cases per 100,000 patient-years [1,2]. The severity of PE ranges from asymptomatic, incidentally discovered subsegmental thrombi to hemodynamically unstable, life-threatening episodes, and sudden death [3,4]. In 1997 Walker and colleagues conducted an epidemiological study suggesting that exposure to clozapine, an agent belonging to the group of the so-called secondgeneration antipsychotic (AP) drugs, significantly increased the risk of PE mortality [5]. Since then, other epidemiological cohort and case control studies provided additional data on this association [6]. A recent systematic review and meta-analysis identified 13 studies, of which only three investigated PE outcomes, while ten estimated the association between AP exposure and risk of a composite outcome which included deep venous thrombosis, femoral vein thrombi, popliteal vein thrombi, iliac vein thrombi, deep vessels of lower extremity thrombophlebitis, and pulmonary embolism [7]. Analysis of the three PE studies failed to detect a significant association between exposure to APs and risk of PE outcomes (odds ratio 4.90, 95% confidence interval 0.77 to 30.98), but the confidence interval was very wide and included the possibility of substantial harm [7]. Therefore, we investigated whether exposure to AP drugs is associated with an increased risk of PE, and ascertained the risk associated with first- and secondgeneration AP drugs, and with exposure to individual drugs. We carried out a nested casecontrol study using a large administrative database in the health system of Lombardy, a region located in northern Italy. As secondary aim, we updated the published meta-analysis with the results of this study, using the same methodology. Methods Setting and data source Lombardy is the largest and the most affluent region in Italy, with a population of around 10 million inhabitants. Lombardy is located in the northernmost part of the country and includes the metropolitan area of Milan, Italys second largest city. The data used for this study were retrieved from the Regional Health Service (RHS) databases of Lombardy [8,9]. These databases include: i) demographic and administrative information on all residents in the Lombardy region; ii) all community (outside the hospital) drug prescriptions reimbursed by the RHS; iii) all public and private hospital discharge forms, with diagnoses according to the ICD-9-CM. According to local regulations on administrative database analyses, no formal approval of the study protocol was required; however, as previously reported for similar analyses [8], to preserve patient privacy, the identification codes from all the databases were converted to anonymous codes, and the conversion table was then destroyed. Study population and design From the regional prescription database we identified all individuals aged 18 starting a new treatment with AP drugs from 1 January 2012 to 31 December 2013. AP drugs were defined as all drugs belonging to the N05A Anatomical Therapeutic Chemical Classification (ATC) group (with the exception of N05AN, lithium). New AP users were individuals with no AP prescriptions in the 12 months before the first prescription issued in the study period. From the group of new AP users, patients with a recorded diagnosis from hospital discharge forms of neoplasm (ICD9-CM 140239), hip fracture (81.xx), pulmonary embolism or deep vein thrombosis (415.xx, 453.xx, 451.1x) in the year before the first AP prescription were excluded. Each member of the cohort was followed from the first AP prescription until the earliest of the following event: outcome of interest (PE), death for any cause, emigration and end of follow-up. Selection of cases and controls Cases were all cohort members who were hospitalized for non-fatal or fatal PE during follow-up (ICD9-CM codes 415.xx). For cases with more than one hospital admission for PE during follow-up, we selected the first record of PE. Up to 20 controls for each case were extracted from the study cohort using incidence density sampling and matched by age at cohort entry and gender. All controls were alive and at risk of the outcome of interest at the date of the first PE in their matched case (index date). Cases and controls with pregnancy (ICD9-CM codes 630677), leg/hip fracture or a diagnosis of neoplasm in the three months before the index date were excluded. In agreement with Parker and colleagues [10], controls with any prescriptions of warfarin or other antithrombotic drug use (ATC code B01AA03/B01AA07) before the index da (...truncated)