Rivastigmine Trial halted due to excess mortality

A randomised trial to assess the efficacy of the cholinesterase inhibitor rivastigmine in treating delirium among critically ill patients was stopped early because of safety concerns. The drug—licensed in the treatment of neuropsychiatric disorders including Alzheimer’s disease and Parkinson’s disease dementia—was no better than placebo in treating delirium; mortality was greater (22%) among those given rivastigmine compared with placebo (8%).

A randomised trial to assess the efficacy of the cholinesterase inhibitor rivastigmine in treating delirium among critically ill patients was stopped early because of safety concerns. The drug—licensed in the treatment of neuropsychiatric disorders including Alzheimer’s disease and Parkinson’s disease dementia—was no better than placebo in treating delirium; mortality was greater (22%) among those given rivastigmine compared with placebo (8%).

The Lancet, Early Online Publication, 5 November 2010

doi:10.1016/S0140-6736(10)61855-7

Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial

Original Text

Maarten MJ van Eijk MD a, Prof Kit CB Roes PhD b, Marina LH Honing MD c, Michael A Kuiper MD d, Attila Karakus MD e, Mathieu van der Jagt MD f, Peter E Spronk MD g, Prof Willem A van Gool MD h, Prof Roos C van der Mast MD i, Prof Jozef Kesecioglu MD a, Dr Arjen JC Slooter MD a

Summary

Background

Delirium is frequently diagnosed in critically ill patients and is associated with adverse outcome. Impaired cholinergic neurotransmission seems to have an important role in the development of delirium. We aimed to establish the effect of the cholinesterase inhibitor rivastigmine on the duration of delirium in critically ill patients.

Methods

Patients (aged ≥18 years) who were diagnosed with delirium were enrolled from six intensive care units in the Netherlands, and treated between November, 2008, and January, 2010. Patients were randomised (1:1 ratio) to receive an increasing dose of rivastigmine or placebo, starting at 0·75 mL (1·5 mg rivastigmine) twice daily and increasing in increments to 3 mL (6 mg rivastigmine) twice daily from day 10 onwards, as an adjunct to usual care based on haloperidol. The trial pharmacist generated the randomisation sequence by computer, and consecutively numbered bottles of the study drug according to this sequence to conceal allocation. The primary outcome was the duration of delirium during hospital admission. Analysis was by intention to treat. Duration of delirium was censored for patients who died or were discharged from hospital while delirious. Patients, medical staff, and investigators were masked to treatment allocation. Members of the data safety and monitoring board (DSMB) were unmasked and did interim analyses every 3 months. This trial is registered with ClinicalTrials.gov, number NCT00704301.

Findings

Although a sample size of 440 patients was planned, after inclusion of 104 patients with delirium who were eligible for the intention-to-treat analysis (n=54 on rivastigmine, n=50 on placebo), the DSMB recommended that the trial be halted because mortality in the rivastigmine group (n=12, 22%) was higher than in the placebo group (n=4, 8%; p=0·07). Median duration of delirium was longer in the rivastigmine group (5·0 days, IQR 2·7—14·2) than in the placebo group (3·0 days, IQR 1·0—9·3; p=0·06).

Interpretation

Rivastigmine did not decrease duration of delirium and might have increased mortality so we do not recommend use of rivastigmine to treat delirium in critically ill patients.

Funding

ZonMw, the Netherlands Brain Foundation, and Novartis.