A double-blind, randomized, placebo-controlled trial of the cholinesterase-inhibiting drug rivastigmine was halted prematurely when it was shown to be ineffective and potentially fatal for critical care patients experiencing delirium, according to a report in the Nov. 5 issue of the Lancet.
Observational studies suggested that rivastigmine, which was approved to treat dementia in patients with Alzheimer’s and Parkinson’s diseases, had potential benefit for delirious critical care patients – especially those for whom antipsychotics, the standard treatment, are contraindicated.
But findings from the randomized, placebo-controlled trial show that rivastigmine is associated with longer duration of delirium and a higher incidence of mortality. Although the higher mortality seen in the treatment arm did not reach statistical significance, it was enough to cause the trial to be halted prematurely.
Dr. Maarten M.J. van Eijk of the department of intensive care medicine at the University Medical Centre Utrecht (the Netherlands) and colleagues assigned 104 critical care patients with delirium to placebo or 1.5-mg rivastigmine twice daily at the onset, titrating to 6-mg rivastigmine twice daily from day 10 onward, as an adjunct to haloperidol. The primary outcome was the length of delirium during the total hospital stay.
Patients’ median age was 68 years in the study arm (54 patients) and 70 years in the control arm (50 patients). Patients and clinicians were blinded to treatment allocation. Because rivastigmine had no reported or suspected interactions with haloperidol, patients were allowed to continue with haloperidol treatment, at various dosages, during the study, and were also allowed to receive lorazepam. After patients recovered from delirium or were no longer discharged, the dose regimen was reversed and the drug was tapered off within 3 days (Lancet 2010 Nov. 5 [doi:10.1016/S0140-6736(10)61855-7]).
The investigators’ findings contrasted sharply with the positive findings of the observational studies, the most recent of which – also by Dutch researchers (BMC Neurology 2008;8:34) – reported a decrease in the severity of delirium in 16 of 17 stroke patients receiving rivastigmine, and concluded that it was a safe alternative to antipsychotics in that patient group.
Dr. van Eijk and colleagues found that the median duration of delirium was longer in the rivastigmine group than in the control group (5 days vs. 3 days). Mortality in the rivastigmine group (n = 12, or 22%) was more than double that in the placebo group (n = 4, or 7%).
"Rivastigmine did not decrease duration of delirium when it was added to standard treatment with haloperidol. Furthermore, rivastigmine was associated with a more severe type of delirium, longer stay in the intensive care unit, and higher mortality than was placebo," Dr. van Eijk and colleagues wrote.
The treatment and control groups’ demographic and clinical characteristics "were well balanced at baseline, and rivastigmine was not associated with any beneficial effects." Because of this, the investigators wrote, they did not challenge the decision by the drug safety and monitoring board to halt the trial.
In an editorial comment accompanying the article, Dr. Yoanna Skrobik of the critical care department of H?pital Maisonneuve-Rosemont in Montreal wrote that the finding of rivastigmine’s ineffectiveness might have to do with the heterogeneous nature of cognitive morbidity in intensive care units.
"How much of the long-term cognitive morbidity can be attributed to sedation depth and the drug used, or to confusion and delirium is thus difficult to establish," Dr. Skrobik said, noting that psychiatric illnesses and postoperative cognitive dysfunction are also widespread in intensive care units (Lancet 2010 Nov. 5 [doi:10/1016/50140-6736(10)61998-8]).
The pathology of delirium may also differ between an elderly patient with Alzheimer’s disease who is not critically ill, Dr. Skrobik noted, and patients in critical care. "Baseline cognitive function is different, as is the degree of systemic inflammation, a potential factor in psychiatric or psychological dysfunction. Neurohormonal transmission might vary significantly from one individual to the next, as might the response to drug treatment."
The study was funded by ZonMw, the Netherlands’ organization for health research and development, the Netherlands Brain Foundation, and Novartis, manufacturer of rivastigmine.
One of Dr. van Eijk’s colleagues reported receiving payment and travel expenses from the Netherlands Society of Psychiatry, the Netherlands Society of Intensive Care, the Health Care Inspectorate, and the University of Amsterdam. Dr. Skrobik declared having no conflicts of interest.