Which antipsychotic exposes the patient to the lowest risk of venous thromboembolism?
Fråga: Which antipsychotic exposes the patient to the lowest risk of venous thromboembolism?
Sammanfattning: A number of observational studies indicate that antipsychotic drugs increase the risk of venous thromboembolism. The mechanism in unclear, but may involve known antipsychotic side-effects such as sedation, weight increase, and metabolic disturbances. In addition, the association between antipsychotics and VTE may have been influenced by various types of bias. Compared to first-generation antipsychotics, the risk seems to be higher with second-generation antipsychotics and clozapine in particular. However, the risk may be low in users of the second-generation antipsychotic aripiprazole.
Svar: There is a well-established association between antipsychotic use and an increased risk of venous thromboembolism (VTE), but the mechanism underlying this association is yet unclear. Mechanisms that have been proposed include physical inactivity due to drug-induced sedation, weight increase, increased levels of antiphospholipid antibodies, enhanced platelet aggregation, hyperhomocysteinaemia and hyperprolactinaemia. In addition, it has been suggested that the psychotic disorders themselves could increase the risk of VTE, forming the basis for potential confounding by indication (1). Several studies have indicated an increasing risk with increasing antipsychotic doses, supporting a causal relationship (1, 2, 4).
Early evidence of the association between antipsychotic therapy and VTE consisted mainly of case reports and small studies, but a systematic review from 2012 identified 12 reasonably large (28 to 76814 cases per study) observational studies published after the year 2000. Although nine of these studies indicated a significant association between antipsychotic therapy and VTE, the risk estimates varied widely with relative risks ranging from 1.2 to 10.5 (1). The smallest significant excess risk was observed in a well-powered study (76814 cases) controlling for a large number of potential confounders, including diabetes, obesity and psychotic disorders. Notably, controlling for obesity and diabetes means that the risk estimate may not account for many cases of VTE mediated through antipsychotic-induced metabolic disturbances (2).
According to a meta-analysis of seven case-control studies including more than 31000 cases and 140000 controls, antipsychotic treatment significantly increases the risk of VTE with an odds ratio of 2.4. However, the analysis indicated publication bias with selective publication of positive studies and the pooled estimate may consequently overestimate the actual risk of VTE (3).
Attempts to compare different antipsychotics with regard to VTE risk has generally indicated an increased risk associated with second-generation (SGA) compared to first-generation antipsychotics (FGA). Among the FGAs, most studies indicate that treatment with high-dose antipsychotics (e.g. chlorpromazine, levomepromazine and thioridazine) confer a higher risk compared to low-dose drugs (e.g. flupenthixol, haloperidol and zuclopenthixol) (1).
In contrast, a newly published Taiwanese study based on data from 2 162 cases and 12966 controls indicated a higher risk of VTE during the first month of treatment with low-dose antipsychotics (OR 3.4) compared to high-dose drugs (OR 2.9). During long-term treatment, neither high- nor low-dose FGAs increased the risk of VTE, while SGAs increased the risk significantly both short-term (OR 4.0) and long-term (OR 1.5). Although a number of potential confounders were controlled for in this study, metabolic disturbances commonly associated with SGA were not among them (4).
The risk profiles of individual antipsychotic drugs have not been thoroughly investigated, but a number of studies have showed a particularly high risk of VTE in users of clozapine, largely accounting for the risk difference between SGAs and FGAs (1, 5). Other antipsychotic drugs that have been individually associated with increased risk of VTE include chlorpromazine, haloperidol, olanzapine, quetiapine, risperidone, sertindole and ziprasidone, but the relative order of these drugs is unclear (1, 2). Although the risk of VTE is allegedly highest in users of second generation antipsychotics, the SGA aripiprazole has been said to carry a particularly low risk (6) and in the study by Allenet et al, aripiprazole was not associated with an increased risk of VTE (OR 0.98) (2).
Regardless of the risk profile of individual antipsychotics, it is crucial that the anticoagulative treatment is reinstated as soon as possible in this patient. Jönsson AK, Spigset O, Hägg S. Venous thromboembolism in recipients of antipsychotics: incidence, mechanisms and management. CNS Drugs 2012;26(8):649-62 Allenet B, Schmidlin S, Genty C, Bosson JL. Antopsychotic drugs and risk of pulmonary embolism. Pharmacoepidemiol Drug Saf 2012;21(1):42-8 Zhang R, Dong L, Shao F, Tan X, Ying K. Antipsychotics and venous thromboembolism risk: a meta-analysis. Pharmacopsychiatry 2011;44(5):183-8 Wu, CS, in CC, Chang CM, Wu KY, Liang HY, Huang YW, Tsai HJ. Antipsychotic treatment and the occurrence of venous thromboembolism: a 10-year nationwide registry study. J Clin Psychiatry 2013;74(9):918-24 Drugline no. 22407 (year 2005) Drugline no. 22397 (year 2005)
Referenser:- Jönsson AK, Spigset O, Hägg S. Venous thromboembolism in recipients of antipsychotics: incidence, mechanisms and management. CNS Drugs 2012;26(8):649-62.
- Allenet B, Schmidlin S, Genty C, Bosson JL. Antopsychotic drugs and risk of pulmonary embolism. Pharmacoepidemiol Drug Saf 2012;21(1):42-8.
- Zhang R, Dong L, Shao F, Tan X, Ying K. Antipsychotics and venous thromboembolism risk: a meta-analysis. Pharmacopsychiatry 2011;44(5):183-8.
- Wu, CS, in CC, Chang CM, Wu KY, Liang HY, Huang YW, Tsai HJ. Antipsychotic treatment and the occurrence of venous thromboembolism: a 10-year nationwide registry study. J Clin Psychiatry 2013;74(9):918-24
- Drugline no. 22407 (year 2005)
- Drugline no. 22397 (year 2005)