 |
 |
5th February 2009
An observational study from Tennessee suggests that typical and atypical antipsychotic drugs approximately double the risk of sudden cardiac death. The absolute increase is approximately an extra 14 per 10,000 patient years overall, although some patients may be at higher risk.
Action
Healthcare professionals should ensure that the appropriate measures and resources are in place to undertake regular ECG monitoring for those people taking antipsychotics who may be at greater risk of developing cardiac arrhythmias. Further guidance is available from the MHRA. Prescribers should be particularly vigilant for ECG-changes and clinical signs suggestive of cardiac arrhythmia in those patients who are at particular risk due to their concomitant medicines or other causes. If antipsychotics are to be used above BNF doses, prescribers should follow the recommendations of the Royal College of Psychiatrists.
What is the background to this?
The risk of cardiac arrythmias associated with antipsychotics is well established and has been previously highlighted by the MHRA. Furthermore, controlled epidemiologic studies have shown a dose-related increased risk of sudden cardiac death associated with the use of first generation (‘typical’). antipsychotics. However, until now, it was not known whether second generation (‘atypical’) antipsychotics carry a greater, lesser or similar risk to first generation agents. This retrospective cohort study examined the rates of sudden cardiac death in users, former users and non-users of antipsychotics among Tennessee Medicaid patients in the US. Sudden cardiac death was defined as a sudden pulseless condition that was fatal, that was consistent with a ventricular tachyarrhythmia and that occurred in the absence of a known non-cardiac condition as the proximate cause of death.
What does this study claim?
Among non-users, the adjusted incidence rate of sudden cardiac death was 14.3 per 10,000 person years. The adjusted incidence rate among former-users was not statistically significantly different from non-users (incidence rate ratio [IRR] 1.13, 95% confidence interval [CI] 0.98 to 1.30, P=0.08). However, the incidence rate was approximately doubled in current users of typical antipsychotics (IRR 1.99, 95%CI 1.68 to 2.34, P<0.001) and current users of atypical antipsychotics (IRR 2.26, 95%CI 1.88 to 2.72, P<0.001). The rate ratio increased with increasing dose. The baseline risk of sudden cardiac death was also higher in older people, so the absolute increase in risk would also be greater in older people.
A limitation of the study is the use of thioridazine, which is no longer available in the UK but which contributed 18% of the total person years exposure to typical antipsychotics in the study. Thioridazine was found to be associated with a greater IRR for sudden death (3.19, 95%CI 2.41 to 4.21) than haloperidol (IRR 1.61, 95%CI 1.16 to 2.24). This may have slightly increased the overall IRR for typical antipsychotics, but probably not to a very large extent.
How does this fit with other evidence?
NICE guidance on schizophrenia (December 2002) recommends that medication should be used as part of a package of care and that second-generation antipsychotics should be considered in the choice of first-line agents, mainly because of a lower risk of extrapyramidal symptoms. This guidance is currently being updated, with publication expected in March 2009.
In the consultation draft of the updated full NICE guideline on schizophrenia, NICE concludes that, in 72 RCTs involving 16,556 participants with an acute exacerbation or recurrence of schizophrenia, there was no evidence that any particular antipsychotic had a superior risk/benefit profile, when compared to any other antipsychotic.
So what?
When antipsychotics are used at lower doses in younger people with schizophrenia who do not have a particularly high baseline risk for sudden cardiac death such as a prolonged QT interval, this increased risk may be less clinically significant. However, in older people, and when higher doses of antipsychotics are used either alone or in combination , the absolute risks become more clinically important: The Royal College of Psychiatrists has recommended that when drugs are used above BNF doses, an ECG is used to exclude untoward abnormalities such as prolonged QT interval. Healthcare professionals should ensure that the appropriate measures and resources are in place to undertake regular ECG monitoring for those people taking antipsychotics who may be at greater risk of developing cardiac arrhythmias. Further guidance is available from the MHRA. Prescribers should be particularly vigilant for ECG-changes and clinical signs suggestive of cardiac arrhythmia in those patients who are taking drugs known to increase plasma levels of antipsychotics, concomitant medicines which have intrinsic potential to prolong the QTc interval (e.g. erythromycin, amiodarone) and in patients who are at greater inherent risk of experiencing cardiac arrhythmias.
The study findings serve to show that atypical antipsychotics carry many risks similar to typical antipsychotics. We have recently blogged about the increased risk of death due to stroke associated with antipsychotic use in dementia, where the absolute risks are substantially greater.
Further information on the management of schizophrenia is available on the schizophrenia section of NPC.
Study details
Ray W et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. New Engl J Med 2009;360:225-35
Patients, intervention and comparison: 44,218 users of single typical antipsychotics, 46,089 users of single atypical antipsychotics and 186,600 matched controls, aged between 30 and 74 years, drawn from the Tennessee Medicaid database between1st January 1990 and 31st December 2005. Patients had to have been enrolled in Tennessee Medicaid for at least 730 days (two years).
Outcome: Among non-users, the adjusted incidence rate of sudden cardiac death was 14.3 per 10,000 person years. The adjusted incidence rate among former-users was not statistically significantly different from non-users (incidence rate ratio [IRR] 1.13, 95% confidence interval [CI] 0.98 to 1.30, P=0.08). However, the incidence rate was approximately doubled in current users of typical antipsychotics (IRR 1.99, 95%CI 1.68 to 2.34, P<0.001) and current users of atypical antipsychotics (IRR 2.26, 95%CI 1.88 to 2.72, P<0.001). The IRR among users of typical antipsychotics increased from 1.31 (95%CI 0.97 to 1.77) at low doses to 2.42 (95%CI 1.91 to 3.06) at high doses (P<0.001 for the dose response relationship). Among users of atypical antipsychotics the IRR increased from 1.59 (95%CI 1.03 to 2.46) to 2.86 (95%CI2.25 to 3.65). Overall unadjusted rates increased from 4.7 deaths per 10,000 person years among patients aged 30 to 34 at baseline, to 47.6 per 10,000 person years for those aged 70 to 74 at baseline, and was more than twice as high in men as women (27.1 vs 12.9 deaths per 10,000 person years).
Sponsorship: Supported by grants from the National Heart, Lung and Blood Institute and the Agency for Healthcare Quality and Research Centers for Education and Research on Therapeutics
Please comment on this blog in the NPC discussion rooms, or using our feedback form