Table 2.
Case–control studies investigating the association between VTE and antipsychotic agents
| Study, year | Study design | Data source | Time period | Total population | Study population | Age (years) | Case definition | Previous VTE excluded | Results (95% CI) |
|---|---|---|---|---|---|---|---|---|---|
| General patient populations | |||||||||
| Zornberg and Jick, 2000 [13] | Nested case–control study | The GPRD, UKa | 1990–1998 | 29,952 users of AP in the UK | 42 cases of VTE and 172 controls | < 60 | Patients with a first-ever recorded VTE | Yes | aOR, FGA: 7.1 (2.3–22.0) LP FGA: 24.1 (3.3–172.7) HP FGA: 3.3 (0.8–13.2) |
| Lacut et al., 2007 [33] | Case–control study | Hospital-based, case records, interviews, France | 2000–2004 | All patients hospitalised due to VTE | 677 cases and 677 controls | ≥ 18 | All patients hospitalised due to VTE | Yes for controls, no for cases | OR, AP: 3.5 (2.0–6.2) FGA: 4.1 (2.1–8.2) SGA: 2.7 (0.7–10.0) |
| Masopust et al., 2007 [34] | Case–control study | Electronic case records, one university hospital, Czech Republic | 1996–2004 | All patients hospitalised at an internal medicine department | 266 cases and 274 controls with hypertension | 18–60 | Patients hospitalised due to VTE or hypertension (controls) | Not stated | OR, AP: 2.8 (1.0–7.6) |
| Jönsson et al., 2009 [35] | Population-based case–control study | Hospital discharge registries and prescription database, Denmark | 1997–2005 | All 1.1 million inhabitants in two counties | 5999 cases (3823 DVT, 2176 PE) and 59,990 matched controls | All ages | Patients with a first-time diagnosis of VTE | Yes | aOR, AP: 2.0 (1.7–2.3) LP FGA: 2.1 (1.5–3.0) HP FGA: 1.8 (1.5–2.3) SGA: 2.5 (1.9–3.3) |
| Parker et al., 2010 [36] | Population-based nested-case control study | The QResearch primary care database, UK | 1996–2007 | All 7.27 million patients registered by 453 UK GPs | 25,532 cases (15,975 DVT, 9557 PE) and 89,491 matched controls Chlorpromazine: 113 cases Haloperidol: 149 cases Olanzapine: 102 cases Prochlorperazine: 1525 cases Quetiapine: 58 cases Risperidone: 148 cases Trifluoperazine: 82 cases |
16–100 | Patients with a first ever recorded VTE | Yes | aOR, any AP use: 1.3 (1.2–1.4) Current AP use: 1.6 (1.4–1.8) New AP use: 2.0 (1.7–2.3) FGA: 1.3 (1.2–1.4) LP FGA 2.0 (1.5–2.6) HP FGA 1.7 (1.4–2.2) SGA: 1.7 (1.4–2.2) Chlorpromazine: 1.8 (1.3–2.5) Haloperidol: 2.2 (1.6–3.0) Olanzapine: 1.5 (1.1–2.1) Prochlorperazine: 1.2 (1.1–1.3) Quetiapine: 2.8 (1.8–4.5) Risperidone: 1.2 (0.9–1.7) Trifluoperazine: 1.3 (0.9–1.9) |
| Ishiguro et al., 2014 [37] | Nested case–control study | The CPRD, UK | 1998–2012 | 810,000 patients with at least one filled prescription for any AP during the study period | 868 cases of VTE, 3158 matched controls Chlorpromazine: 5 cases Haloperidol: 5 cases Olanzapine: 16 cases Prochlorperazine: 42 cases Risperidone: 12 cases |
20–59 | Diagnosis of incident VTE | Yes | aOR: Current AP users: 1.3 (1.0–1.6) New AP users: 3.2 (1.6–6.3) FGA: 1.3 (0.9–1.8) LP FGA: 0.7 (0.3–1.5) HP FGA: 1.5 (1.0–2.1) SGA: 1.2 (0.8–1.9) Chlorpromazine: 1.0 (0.4–2.8) Haloperidol: 1.2 (0.4–3.5) Olanzapine: 1.3 (0.7–2.5) Prochlorperazine: 2.2 (1.5–3.2) Risperidone: 1.8 (0.9–3.8) |
| Wu et al., 2013 [38] | Case–control study | National health insurance research database, Taiwan | 2001–2010 | 1,000,000 individuals | 2162 cases of VTE 12,966 matched controls | ≥ 16 | Hospitalisation for VTE or an outpatient VTE with intravenous or subcutaneous anticoagulant therapy | Yes (cases with a VTE in the year 2000 were excluded) | aORs: Current users of AP: 1.5 (1.2–1.9) New users of AP: 3.3 (2.1–5.2) Continuous users of AP: 1.2 (0.9–1.6) New users of LP FGA: 2.9 (1.6–5.2) New users of HP FGA: 3.4 (1.1–10.3) New users of SGA: 4.0 (1.2–12.9) Continuous users: NS differences for either FGA or SGA |
| Wang et al., 2016 [39] | Case–control study | National health insurance research database, Taiwan | 2000–2011 | 316,000 women | 2520 cases and 24,223 matched controls Amisulpride: 6 cases Aripiprazole: 6 cases Clothiapine: 3 cases Droperidol: 5 cases Flupentixol: 53 cases Haloperidol: 48 cases Olanzapine: 10 cases Prochlorperazine: 115 cases Quetiapine: 66 cases Risperidone: 45 cases Sulpiride: 70 cases Thioridazine: 3 cases Trifluoperazine: 5 cases |
≥ 50 | Diagnosis of VTE treated with anticoagulants or thrombectomy | Yes | aORs Current users of AP: 1.9 (1.6–2.2) New users of AP: 2.1 (1.5–2.8) Continuous users of AP: 1.9 (1.6–2.2) FGA: 1.8 (1.5–2.1) SGA: 1.9 (1.4–2.7) Amisulpride: 5.4 (2.0–14.6) Aripiprazole: 9.4 (2.8–31.8). Clothiapine: 4.7 (0.9–24.4) Droperidol: 3.8 (1.1–12.3) Flupentixol: 1.1 (0.8–1.5) Haloperidol: 2.6 (1.8–3.8) Olanzapine: 4.7 (2.2–10.1) Prochlorperazine: 2.7 (2.1–3.4) Quetiapine: 1.9 (1.4–2.5) Risperidone: 2.7 (1.8–3.9) Sulpiride: 1.5 (1.1–2.0) Thioridazine: 1.3 (0.4–4.8) Trifluoperazine: 3.8 (1.3–11.3) |
| Conti et al., 2015 [40] | Case–control study | Healthcare system in Lombardy, Italy | 2012–2013 | 144,000 AP users | 232 cases of PE, 4353 matched controls | ≥ 18 | Diagnosis of PE | No? | aOR current compared with past use AP 2.3 (1.2–4.6). FGA 3.5 (1.7–7.4) SGA 2.0 (1.0–4.0) |
| Premuš Marušič et al., 2017 [41] | Case–control study | Medical records of the Murska Sobota General Hospital, Slovenia | 2007–2011 | 286 patients treated at the surgical department | 144 cases and 142 controls. 21 cases and 15 controls used AP | All | Diagnosis of DVT or PE within 180 days after surgical treatment | Yes | Univariate analysis p = 0.3, not included in the regression analyses |
| Elderly patient populations | |||||||||
| Kleijer et al., 2010 [42] | Time-matched, nested, case–control study | The PHARMO Institute’s record linkage system, The Netherlands | 1998–2008 | 112,000 new users of AP | 1032 cases (367 DVT, 342 PE and 323 outpatients) and 4125 controls | ≥ 60 | VTE diagnosis or start of treatment with LMWH in combination with vitamin K antagonists | No? | aOR, SGA: 0.9 (0.7–1.1) vs. FGA |
| Schmedt and Garbe, 2013 [43] | Case–control study | The German pharmacoepidemiological research database (GePaRD), Germany | 2004–2007 | 73,000 patients with dementia | 1028 cases and 4109 controls | ≥ 65 | Hospitalisations due to VTE | No | aOR, AP: 1.2 (1.0–1.5) FGA: 0.89 (0.6–1.2) SGA: 0.94 (0.7–1.2) FGA and SGA: 1.6 (1.2–2.3) |
| Deceased patient populations | |||||||||
| Walker et al., 1997 [11] | Case–control study | The US national registry of clozapine recipients and National death register, USA | 1991–1993 | 67,000 current and former clozapine users | 396 deaths in 85,399 person-years; 19 deaths due to PE, 18 used AP | 10–54 | Fatal PE | Not stated | RR for current clozapine use compared with previous use = 5.2 |
| Parkin et al., 2003 [44] | Case–control study | Coroner’s records (cases) and GP records (cases and controls), New Zealand | 1990–1998 | All residents in New Zealand aged 15–59 years | 62 cases and 243 GP-based controls | 15–59 | Persons deceased due to VTE | Yes | aOR AP: 13.3 (2.3–76.3) LP FGA: 20.8 (1.7–259.0) |
| Hamanaka et al., 2004 [45] | Retrospective prevalence study with a control group | Medico-legal autopsy records, Japan | 1998–2002 | 1125 forensic autopsies | 34 individuals using AP and 28 with PE | All ages | PE diagnosed at autopsy | NA | aOR AP: 10.5 (4.0–27.9) |
aOR adjusted odds ratio, AP antipsychotics, CI confidence interval, CPRD Clinical Practice Research Datalink, DVT deep vein thrombosis, FGA first-generation antipsychotics, GP general practitioner, GPRD General Practice Research Database, HP high-potency, LP low-potency, LMWH low-molecular weight heparin, NA not applicable, NS non-significant, OR odds ratio, PE pulmonary embolism, RR risk ratio, SGA second-generation antipsychotics, VTE venous thromboembolism
aKnown as the Clinical Practice Research Datalink (CPRD) after March 2012