Abstract and Introduction
Abstract
Objective. To determine whether antipsychotic drugs are associated with an increased risk of venous thromboembolism, and to examine risks by type of antipsychotic, potency, and dose.
Design. Population based nested case-control study.
Setting. The UK QResearch primary care database.
Participants. Patients (cases) with a first ever record of venous thromboembolism between 1 January 1996 and 1 July 2007; each was matched with up to four controls by age, calendar time, sex, and practice.
Main outcome measures. Odds ratios for venous thromboembolism associated with antipsychotic drugs adjusted for comorbidity; concomitant drug exposure.
Results. There were 25 532 eligible cases (15 975 with deep vein thrombosis and 9557 with pulmonary embolism) and 89 491 matched controls from a study population of 7 267 673. Individuals prescribed antipsychotic drugs in the previous 24 months had a 32% greater risk of venous thromboembolism than non-users, despite adjustment for potential risk factors (odds ratio 1.32, 95% confidence interval 1.23 to 1.42). Patients who had started a new drug in the previous three months had about twice the risk (1.97, 1.66 to 2.33). The risk was greater for individuals prescribed atypical rather than conventional drugs (adjusted odds ratio 1.73, 1.37 to 2.17, for atypical drugs; 1.28, 1.18 to 1.38, for conventional drugs). It also tended to be greater for patients prescribed low rather than high potency drugs (1.99, 1.52 to 2.62, for low potency; 1.28, 1.18 to 1.38, for high potency). The estimated number of extra cases of venous thromboembolism per 10 000 patients treated over one year was 4 (3 to 5) in patients of all ages and 10 (7 to 13) for patients aged 65 and over.
Conclusions. There is an association between use of antipsychotic drugs and risk of venous thromboembolism in a large primary care population. The increased risk was more marked among new users and those prescribed atypical antipsychotic drugs.
Introduction
Venous thromboembolism is an important and preventable cause of morbidity and mortality. Up to a quarter of affected patients die within a week, and almost a third of survivors experience long term effects. Some research has indicated that antipsychotic drugs, some of which are also widely prescribed for nausea, vomiting, and vertigo, might be associated with an increased risk of venous thromboembolism. Early case reports led to several studies, but the findings have been inconsistent and the possible association has received little attention.
One case-control study found a sevenfold risk of venous thromboembolism among current users of antipsychotic drugs, and another a 13-fold risk of death from pulmonary embolism. The studies were based on small numbers, excluded older people, and were conducted before the widespread use of atypical antipsychotic drugs. A hospital based case-control study found a 3.5-fold risk associated with antipsychotics, with a lower risk for atypical drugs than for conventional drugs. Two large cohort studies focused on people aged 65 or over who were taking antipsychotic drugs. One found a non-significant overall association, although the subgroup taking butyrophenone conventional drugs showed a 43% increased risk. The other, based on residents of nursing homes, found a doubled risk associated with atypical drugs but no effect with conventional drugs. A further cohort study focused on the atypical clozapine and found that current users had a fivefold risk of death from pulmonary embolism compared with past users.
There are therefore grounds for concern, but considerable uncertainty remains on an association that, if proved, would have important implications. Several plausible biological mechanisms have been suggested, including enhanced aggregation of platelets, raised concentrations of anticardiolipin antibodies, and exacerbation of venous stasis.
We investigated whether antipsychotic drugs are associated with an increased risk of venous thromboembolism and examined risks by type, potency, and dose, adjusting for comorbidity and concomitant drug exposure. We carried out a nested case-control study in a large population based primary care cohort in the United Kingdom.