Table 3.
Cohort studies and drug surveillance 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 | |||||||||
| Allenet et al., 2012 [46] | Cohort study | The Premier’s Perspective’ database, USA | 2006 | Among 29,000,000 adults, including 450,951 patients with at least one AP prescription (46% had psychotic disorders) Aripiprazole: 31,130 users Chlorpromazine: 19,330 users Clozapine: 5366 users Haloperidol: 157,667 users Olanzapine: 69,975 users Risperidone: 99,890 users Quetiapine: 142,964 users Ziprasidone: 40,980 users |
76,814 cases of PE | ≥ 18 | Hospitalisations due to PE | No | aOR, AP: 1.2 (1.1–1.2) FGA 1.2 (1.1–1.3) SGA 1.2 (1.1–1.2) Aripiprazole: 0.98 (0.83–1.15) Chlorpromazine: 1.19 (1.03–1.38) Clozapine: 1.46 (1.05–2.02) Haloperidol: 1.17 (1.11–1.24) Olanzapine: 1.12 (1.03–1.22) Risperidone: 1.15 (1.07–1.23) Quetiapine: 0.97 (0.91–1.04) Ziprasidone: 1.21 (1.07–1.38) |
| Hsu et al., 2015 [47] | Cohort study | National health insurance research database, Taiwan | 1996–2011 | 60,000 patients with schizophrenia and 60,000 control patients without schizophrenia |
161 cases of DVT and 55 cases of PE among patients with schizophrenia 79 cases of DVT and 27 cases of PE among control patients |
> 20 | Diagnoses of VTE | Yes | aHR, FGA users vs. non-schizoprenia patients: for DVT 2.09 (1.55–2.81); for PE 1.93 (1.16–3.22) aHR, SGA users vs. non-schizoprenia patients: for DVT 1.74 (1.05–2.90); for PE 2.42 (1.12–5.24) |
| Ferraris et al., 2017 [48] |
Retrospective cohort study | Electronic database of a tertiary teaching hospital in Buenos Aires, Argentina | 2002–2007 | 1008 new users of AP (66% had dementia, 12 % bipolar disorder, 9% schizophrenia) | 184 cases of VTE | 30–90 | Time to first VTE | Yes | aHR, AP with high risk for sedation/metabolic abnormalities vs. low risk 1.23 (0.74–2.04) aHR, AP with high risk for hyperprolactinaemia and thromboembolism events vs. low risk 0.81 (0.50–1.35) |
| Hippisley-Cox and Coupland, 2011 [49] | Cohort study | The QResearch database England and Wales | 2004–2010 | 2,315,000 patients | 14,756 cases of VTE | 25–84 | VTE diagnosis | Yes | aHR, AP in women 1.55 (1.32–1.81); AP in men 1.84 (1.51–2.23) |
| Nakamura et al., 2017 [50] | Cohort study | The EBM provider healthcare database, Japan | 2008–2013 | 3554 patients diagnosed with VTE in 100 acute care hospitals (10% of all acute care admissions in Japan) | 26 cases of VTE in 350 users of AP vs. 199 cases of VTE in 3204 non-users of AP | All ages | Recurrent VTE diagnosis | No | aHR 1.6 (1.0–2.4) |
| Elderly patient populations | |||||||||
| Ray et al., 2002 [51] | Retrospective cohort study | Healthcare administrative databases: Ontario Drug Benefits database, Canadian Institute for Health Information Discharge Abstract Database, OHIP database, Canada | 1994–2000 | Individuals with prescriptions of AP (n = 23,000), AD (n = 76,000) or TH (n = 33,000) within the OHIP database Haloperidol: 8508 users |
Cases of VTE per 1000 person-years of users: 19.2 for AP, 12.0 for TH and 14.3 for AD | ≥ 65 | Diagnosis of DVT or PE | Yes | aHR, AP: 1.1 (0.95–1.3) vs. TH treatment Haloperidol: 1.4 (1.2–1.7) |
| Liperoti et al., 2005 [52] | Retrospective cohort study | The minimum dataset, Medicare inpatient claims, USA | 1998–1999 | 19,940 new users of APs (73% had dementia, 45% depression, 20% anxiety) and 112,078 non-users in nursing home residents in five states Clozapine/quetiapine: 977 users Risperidone: 7811 users Olanzapine: 2825 users |
28 cases of VTE among FGA AP users 64 cases of VTE in users of SGAs |
≥ 65 | Hospitalisations due to VTE | No | aHR FGAs 1.0 (0.7–1.6) SGAs 2.0 (1.5–2.7) Clozapine/quetiapine 2.7 (1.2–6.3) Risperidone 2.0 (1.4–2.8) Olanzapine 1.9 (1.1–3.3) |
| Dennis et al., 2017 [53] | Cohort study | The Welsh Secure Anonymised Information Linkage databank | 2003–2011 | 9674 patients newly diagnosed with dementia | 37,535 exposed to AP | ≥ 65 | VTE | No | PERR: AP 1.95 (1.83–2.0) |
| Deceased patient populations | |||||||||
| Jönsson et al., 2008 [54] | Medico-legal autopsy series | Swedish medico-legal autopsy register | 1992–2005 | 14,439 medico-legal autopsy cases | PE was recorded as the cause of death in 279 participants, 33 of whom used AP | 18–65 | Fatal PE determined by a forensic pathologist | Yes | aOR LP FGA: 2.39 (1.46–3.92) SGA 6.91 (3.95–12.10) |
| Adverse drug reaction surveillance programmes | |||||||||
| Hägg et al., 2000 [12] | Case series | The Swedish ADR database | 1989–2000 | All ADR case records 1989–2000 | 12 cases of VTE during treatment with clozapine (8 patients had schizophrenia, 4 psychosis), 3 cases of VTE during treatment with all other APs | 18–60 | Reported VTE | A conservative risk estimate was 1 case per 2000–6000 clozapine-treated patients | |
| Hägg et al. 2008 [55] | Data mining | The WHO ADR database, worldwide | 1975–2004 | 3.2 million ADR case records | 734 cases of VTE during APs treatment | All ages | Reported VTE | Significantly more VTE events than expected reported for clozapine (n = 385), olanzapine (n = 99). sertindole (n = 6) and zuclopenthixol (n = 10) | |
| Letmaier et al., 2017 [56] | Cohort study | Multicentre drug surveillance programme for psychiatric inpatients: Germany, Austria and Switzerland | 1993–2011 | 264,422 treated patients with AP (49 % had schizophrenia, 25% mood disorders, 26% other) in 99 psychiatric hospitals Amisulpride: 10,665 users Aripirazole: 8421 users Chlorprothixene: 12,282 users Clozapine: 33,213 users Flupentixol: 3032 users Fluphenazine: 3032 users Haloperidol: 36,156 users Levomepromazine: 11,851 users Melperone: 16,769 users Olanzapine: 41,903 users Perazine: 15,168 users Pipamperone: 18,102 users Promethazine: 14,006 users Prothipendyl: 10,778 users Quetiapine: 42,171 users Risperidone: 39,749 users Zuclopenthixol: 9486 users |
89 inpatients with VTE |
All ages | Diagnosis of VTE | No | Overall 3.4 cases per 10,000 inpatient admissions Amisulpride: 3.8 cases per 10,000 Aripiprazole: 0 cases per 10,000 Chlorprothixene: 1.6 cases per 10,000 Clozapine: 4.8 cases per 10,000 Fluphenazine: 0 cases per 10,000 Flupentixol: 1.5 cases per 10,000 Haloperidol: 5.3 cases per 10,000 Levomepromazine: 4.2 cases per 10,000 Melperone: 3.0 cases per 10,000 Olanzapine: 2.9 cases per 10,000 Perazine: 2.0 cases per 10,000 Pipamperone: 6.1 cases per 10,000 Promethazine: 3.6 cases per 10,000 Prothipendyl: 4.6 cases per 10,000 Quetiapine: 1.7 cases per 10,000 Risperidone: 5.5 cases per 10,000 Zuclopenthixol: 4.2 cases per 10,000 |
AD antidepressant, ADR adverse drug reaction, aHR adjusted hazard ratio, aOR adjusted odds ratio, AP antipsychotics, CI confidence interval, DVT deep vein thrombosis, EBM evidence-based medicine, FGA first-generation antipsychotics, LP low potency, OHIP Ontario Health Insurance Plan, PE pulmonary embolism, PERR prior event rate ratio, TH thyroid hormone, SGA second-generation antipsychotics, VTE venous thromboembolism