Antipsychotics and risk of venous thromboembolism: A population-based case-control study

Clinical Epidemiology downloaded from https://www.dovepress.com/ by 118.216.90.192 on 06-Jul-2020 For personal use only. ORIGINAL RESEARCH Antipsychotics and risk of venous thromboembolism: A population-based case-control study Anna K Jönsson 1 Erzsebet Horváth-Puhó 2 Staffan Hägg 3 Lars Pedersen 4 Henrik Toft Sørensen 4 1 Nordic School of Public Health, Gothenburg, Sweden; 2 Centre for Registry Research, Aarhus C, Denmark; 3 Division of Clinical Pharmacology, Linköping University, Linköping, Sweden; 4 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus C, Denmark Abstract: During the last decade, the risk of venous thromboembolism (VTE) has been reported in users of antipsychotic drugs. However, the reports have been inconclusive. This study aimed to determine the relative risk of VTE in antipsychotic drug users. Using data from medical databases in North Jutland and Aarhus Counties, Denmark, and the Danish Civil Registration System, we identified 5,999 cases with a first-time diagnosis of VTE and, based on risk set sampling, 59,990 sex- and age-matched population controls during 1997–2005. Users of antipsychotic drugs were identified from population-based prescription databases and categorized based on filled prescriptions prior to admission date for VTE or index date for controls as current (at least one prescription within 90 days), recent (at least one prescription within 91–180 days), former (at least one prescription within 181–365 days) or nonusers (no recorded prescription within 365 days). Compared with nonusers, current users of any antipsychotic drugs had an increased risk of VTE (adjusted relative risk [ARR]: 1.99, 95% confidence interval [CI]: 1.69–2.34). Former users of any antipsychotic drugs had a nonsignificant elevated risk of VTE compared with nonusers (ARR: 1.54, 95% CI: 0.99–2.40, p-value: 0.056). In conclusion, users of antipsychotic drugs have an increased risk of VTE, compared with nonusers, which might be due to the treatment itself, to lifestyle factors, to the underlying disease, or to residual confounding. Keywords: antipsychotic agents, venous thromboembolism, adverse effects, case-control study Introduction Correspondence: Anna K Jönsson Nordic School of Public Health, PO Box 121 33, SE-402 42 Gothenburg, Sweden Tel +46 31 693 989 Fax +46 31 691 777 Email Schizophrenia is a chronic, severe, and disabling disorder with a lifetime prevalence of about 0.5% in the general population.1 Patients suffering from schizophrenia and other psychotic disorders have increased morbidity and mortality from cardiovascular disease.2 During the past decade, several studies3–12 have reported that treatment with antipsychotic drugs also may be associated with an increased risk of venous thromboembolism (VTE). The hypothesized association between first-generation (conventional) antipsychotic drugs and VTE is based primarily on one case-control study3 where Zornberg and colleagues observed a risk of VTE for patients aged less than 60 years currently treated with first-generation antipsychotics, compared with former users of these drugs. As only a limited number of study subjects were taking second-generation (atypical) antipsychotics, the risk of VTE in patients using these newer drugs could not be evaluated in that study. The suggested association between second-generation antipsychotics and VTE is primarily supported by a cohort study4 of nursing home residents aged 65 years or older where a risk of VTE was observed in new users of second-generation antipsychotics, compared to nonusers. However, in that study no increased risk of VTE in users of first-generation antipsychotics was found. Ray and colleagues12 did not find an association with VTE in a cohort of patients 65 years of age or older treated with any antipsychotic drug, except for patients receiving haloperidol, Clinical Epidemiology 2009:1 19–26 © 2009 Jönsson et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Powered by TCPDF (www.tcpdf.org) 19 Jönsson et al Clinical Epidemiology downloaded from https://www.dovepress.com/ by 118.216.90.192 on 06-Jul-2020 For personal use only. compared to users of thyroid hormones. Available data on the association between antipsychotic drug use and VTE thus remains conflicting. We undertook this population-based study to investigate the hypothesized increased risk of VTE in current, recent and former users of first-generation (low-potency and high-potency) and second-generation antipsychotic drugs. Methods This population-based case-control study was conducted within the counties of Aarhus and North Jutland, Denmark, from January 1, 1997 to December 31, 2005. The two counties have a combined population of 1.1 million, representing approximately 20% of the Danish population. In Denmark use of civil registration numbers (permanent unique identifiers provided at birth to each Danish citizen) allows unambiguous linkage between all demographic and healthcare registries.13 Hospital registries contain records of discharges from all nonpsychiatric hospitals since 197713 and since 1995 for all outpatient visits. Their files include civil registration number, dates of hospital admission and discharge, and up to 20 discharge diagnoses and procedures, coded according to the international classification of diseases, 8th revision (ICD-8) until the end of 1993 and 10th revision (ICD-10) thereafter. The Danish National Health Service provides tax-supported health care for all residents of Denmark, including partial reimbursement of the cost of prescribed medications.13 The pharmacies serving Aarhus and North Jutland counties employ electronic accounting systems, used primarily to secure reimbursement from the National Health Service. For each filled prescription of reimbursed drugs, data on the customer’s civil registration number, type and amount of drug prescribed according to the Anatomical Therapeutic Chemical (ATC) classification system, and date of dispensing are transferred from the pharmacies to prescription databases established in 1989 in North Jutland County and in 1996 in Aarhus County. We used the hospital registries to identify all patients with a first-time diagnosis of VTE, ie, deep vein thrombosis in a lower limb (ICD-8 code: 451.00 and ICD-10 codes: I80.1, 180.2, 180.3) and/or pulmonary embolism (ICD-8 code: 450.99 and ICD-10 code: 126). To control for the increased risk of VTE observed in immobilized patients,14 we excluded patients with VTE as a secondary admission diagnosis. In a second analysis only patients with a primary idiopathic VTE were included and patients with a secondary VTE,15 ie, with well-established predisposing conditions defined as surgery, major trauma, fractures, pregnancy within the prior 20 Powered by TCPDF (www.tcpdf.org) three months, pre-existing cancer, or a cancer diagnosis within the three (...truncated)