Donepezil and galantamine have only been studied in open-label studies or small scale clinical trials in PDD (). Rivastigmine has been studied in large randomized, placebo-controlled clinical trials in DLB (McKeith et al 2000
) and PDD (Emre et al 2004
) (). The data available for rivastigmine has led to the approval of this medication in the treatment of PDD in Europe, the United States and elsewhere.
Placebo-controlled cholinesterase inhibitor trials in PDD and DLB
McKeith et al (2000)
studied the efficacy of rivastigmine in DLB. In this randomized, double-blind, placebo-controlled study, participants were given placebo or titrated up to 12 mg/day of rivastigmine for 20-weeks followed by a 3-week washout period. Assessments were made at baseline, and at 12-, 20-, and 23-weeks. Neuropsychiatric testing and computerized cognitive assessments were performed at each session. Significant clinical and cognitive performance improvements were noted in those receiving rivastigmine as compared with placebo. Thirty-seven subjects (63%) in the rivastigmine group showed at least a 30 percent improvement from baseline as compared to only 18 subjects (30%) of the placebo group. Patients improved most in the areas of apathy and indifference and had fewer hallucinations than those receiving placebo.
As previously discussed, it is becoming more evident that DLB and PDD are on a continuum of disease, with significant overlap in terms of clinical and cognitive signs and symptoms (Aarsland et al 2005
; Galvin et al 2006
; Padovani et al 2006
). Given the obvious clinical benefits of rivastigmine in DLB (McKeith et al 2000
), this led to further study in patients defined as having PDD.
In an open label trial by Reading et al (2001)
, twelve patients with PD-related cognitive impairment and psychosis were given rivastigmine at an initial dose of 1.5 mg twice daily and then titrated to 6 mg twice daily or the highest tolerated dose. Patients were assessed at 8-weeks after the maximum titration level was reached and once again 6-weeks after that period. The drug was discontinued at that point and participants were assessed once again 3-weeks after withdrawal of rivastigmine. At each session, the Folstein Mini-Mental Status Exam (MMSE) was utilized as a measure of cognition and the Unified Parkinson’s Disease Rating Scale (UPDRS) was administered to evaluate the motor symptoms of PD. Neuropsychiatric symptoms were evaluated using the Neuropsychiatric Inventory (NPI), which evaluates behaviors over the preceding four weeks. Cognitive assessment utilizing the MMSE revealed significant improvement of 5 points in patients on rivastigmine relative to their baseline (Z = 2.81, p < 0.005). Motor symptoms and signs were unchanged as measured by UDPRS (Z = 1.18, p > 0.2). NPI scores were also significantly lowered (improved) from baseline on treatment (Z = 2.85, p < 0.004). Patients worsened significantly three weeks after withdrawal of the rivastigmine (Reading et al 2001
Giladi et al (2003)
also studied the efficacy of rivastigmine in the treatment of PDD. In this open label study, 20 of 28 patients completed 26-weeks of treatment with rivastigmine therapy (as tolerated up to 12 mg/day). The MMSE and Alzheimer’s Disease Assessment Scale (ADAS-cog) were used as cognitive measures and the UPDRS for documenting Parkinsonian features. Patients were assessed prior to starting therapy, at 12 and 26-weeks while on rivastigmine, and 8-weeks after withdrawal of therapy. Eight of the 28 patients dropped out secondary to side effects. An increase in UDPRS score was observed from baseline to week 26 (p > 0.06) and a non-significant improvement was noted from week 26 to 8-weeks after treatment washout. Significant improvement was noted in the area of the attentional components of the MMSE at week 26 (p < 0.002). In terms of the ADAS-cog, a significant increase in total score (worsening) was noted throughout the study period (p = 0.002).
The authors indicated that the objective cognitive measures (MMSE and ADAS-cog) did not at all reflect the clinical impressions of the caregivers for the patients in the study. In particular, caregivers seemed surprise by the deterioration experienced after washout. This, again, suggests the need for a cognition assessment tool that is validated and best utilized in PD. Giladi et al (2003)
also noted increased tremor in eleven of the original 28 participants in the study and dose reduction was required.
In this study, it would be expected for patients to worsen on the UPDRS over 6-months whether they were on an AChE inhibitor or not. A non-significant trend for improvement in the UPDRS scores following washout, however would make one consider that rivastigmine negatively influenced motor performance. An increase in tremor and parkinsonism was a legitimate concern in this study given we still use anticholinergics for some patients with PD (certainly not demented ones, though!) (Morgan and Sethi 2005). There were prior case reports of worsening of tremor and parkinsonism in PD patients treated with AChE (Richard et al 2002
). The results of the Reading et al (2001)
and Giladi et al (2003)
studies indicated further need to study the effects of this drug on cognition and parkinsonism in PDD in a prospective, double-blind, placebo-controlled fashion.
In 2003, Fogelson et al (2003)
performed another open label study examining the effects of rivastigmine on quantitative EEG (qEEG) in PDD patients (n = 19), given they frequently have a slowing of alpha activity on EEG. Patients were treated with rivastigmine at an initial dose of 3 mg/day and titrated to a dose of 12 mg/day or highest tolerated dosage. Quantitative EEG recordings were performed prior to introduction of rivastigmine and repeated when the patients had been on treatment for 12-weeks. A significant increase in the relative alpha activity was noted after treatment with rivastigmine (p = 0.019), however, no correlation between qEEG changes and cognitive improvement was identified (Fogelson et al 2003
). It is difficult, therefore, to determine whether these qEEG changes were due to improvement in cognitive state rather than just an increase in arousal.
A sound neuropathological and pharmacological basis and promising open label studies were followed by the publication of a multi-center, placebo-controlled, double-blind study in 541 patients with PDD (Emre et al 2004
). PD was diagnosed using the UK PD Brain Bank Criteria and dementia was diagnosed using DSM-IV criteria. Participants were randomly assigned to receive placebo or 3–12 mg (titrated to the maximum tolerated dose over a 16-week dose escalation period) of rivastigmine divided twice daily for 24-weeks. Patients were randomized 2:1 to rivastigmine and placebo, respectively. The primary outcome measures were the ADAS-cog scores as in previous open label studies (Fogelson et al 2003
; Giladi et al 2003
) and the Alzheimer’s Disease Cooperative Study-Clinician’s Global Impression of Change (ADCS-CGIC). There were six secondary outcome measures: Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL), NPI, MMSE, Cognitive Drug Research Power of Attention tests (CDR), Delis-Kaplan Executive Function System (D-KEFS) verbal fluency test, and the Ten Point Clock-Drawing Test. Safety monitoring included recording of adverse events, monitoring ECGs and laboratory data, vital signs and body weight. Patients were also assessed for changes in parkinsonism from baseline scores at weeks 16 and 24 using the UPDRS part III (motor section) score.
Patients were included in the efficacy analysis if they underwent a baseline evaluation and if they took one dose of study medication followed by an assessment of the one of the efficacy variables after baseline (regardless if they were taking study medication at the time). If no follow-up information was available Emre et al (2004)
used the last-observation-carried-forward method to impute missing values for missing follow-up information.
Approximately 30%–35% of patients enrolled in the study suffered with co-morbid psychiatric disorders (including depression, anxiety, and psychosis) (Emre et al 2004
). The average age of patients was approximately 72 with PD diagnosis 9-years earlier on average. Essentially all of the patients were Caucasian and approximately 2/3 were men. The mean time since the diagnosis of PDD for patients entering the study was approximately 13–15 months. There were no significant demographic differences between the two treatment groups.
As compared to patients in the placebo group, patients who received rivastigmine demonstrated significant improvements in ADAS-cog and ADCS-CGIC scores (primary efficacy variables) (Emre et al 2004
). Patients that were treated with rivastigmine had a mean improvement of 2.1 points in the ADAS-cog, while patients in the placebo group had a 0.7 point worsening (p, 0.001). Clinically meaningful improvement was observed in the investigator rated ADS-CGIC in 19.8% or rivastigmine patients and 14.5% in placebo-treated patients, while clinically meaningful worsening was evident in 13.0% and 23.1 percent, respectively (p = 0.007). At week 24, rivastigmine provided improvement in all six secondary efficacy variables relative to the baseline evaluation, while placebo-treated patients remained the same (NPI) or worsened (ADCS-ADL, MMSE, CDR, D-KEFS, Ten Point Clock-Drawing Test) (Emre et al 2004
). These benefits should be considered moderate and in-line with other clinical trials of AChE inhibitors in AD.
A total of 410 out of 541 patients enrolled completed the study. Ninety-nine patients dropped out of the study in the rivastigmine arm with 32 dropping-out in the placebo arm. Approximately two-thirds of the drop-outs in the rivastigmine arm were due to adverse events and less than half of the drop-outs in the placebo arm were due to the same. Cholinergic symptoms typical of AChE inhibitors were the most common adverse events, with nausea reported by 29% of rivastigmine – vs 11.2% of placebo-treated patients (p < 0.001) and vomiting by 16.6% vs 1.7% respectively. In general, Parkinsonian symptoms as a whole were more often reported by patients in the rivastigmine group relative to placebo (27.3% vs 15.6%, p = 0.002). Tremor (10.2% vs 3.9%) and dizziness (5.8% vs 1.1%) were also reported more often as an adverse event in rivastigmine-treated patients. Tremor only caused withdrawal of 1.7% of patients in the rivastigmine group and no one in the placebo group (p = 0.19). There was no significant difference in UPDRS motor scores and tremor related items between the groups, however. Interestingly, hallucinations (4.7% vs 9.5%) and orthostatic hypotension (1.7% vs 5.0%) were reported more often in patients treated with placebo.
In a letter to the editor, Harada et al (2005)
argued that the number needed to treat in order to reach what Emre et al (2004)
defined as “clinically meaningful improvement” does not outweigh the side effects experienced by the participants in the study. Harada et al (2005)
only considered those who had “clinically meaningful benefit” in their analysis, however, and an important factor in any progressive neurodegenerative dementia is how many patients were prevented from “clinically meaningful worsening” as well.
The results of the Emre et al (2004)
study are encouraging for the use of rivastigmine in PDD, however the efficacy is modest. Adverse events are common with rivastigmine and typically cholinergic in nature, however they usually do not result in discontinuation of the drug. This study was hampered by lack of a validated assessment tool for PDD. The ADAS-cog and the ADCS-CGIC as primary efficacy variables are appropriate, however there needs to be further validation of this scale in PDD. Fortunately, six additional tests of cognitive domains that would be impaired in PDD were also used (CDR, etc.). The finding of fewer reported hallucinations in the rivastigmine-treated arm is interesting given this drug may not only provide stabilization and slower decline of cognitive function in PDD, it may also help reduce hallucinations, which can be quite troubling for patients and caregivers alike.
Another concern is the cost of this drug relative to the benefit. Is the modest benefit obtained enough to delay nursing home placement and is it cost-effective over time? Should NMDA-receptor antagonists such as memantine be added to PDD as it advances? Are the other AChE inhibitors equally efficacious in PDD?
There was an open-label extension to the Emre et al (2004)
study published recently by Poewe et al (2006)
. Of 433 patients that completed the double-blind trial, 334 entered and 273 completed the active treatment extension study (3–12 mg rivastigmine/day). At 48-weeks the ADAS-cog score had improved by 2 points above baseline for the entire group of patients. Patients in the placebo treatment arm in the original Emre et al (2004)
trial also had a 2-point improvement in their ADAS-cog score. The safety profile of rivastigmine in the open label extension was similar to the double-blind phase (Poewe et al 2006
Wesnes et al (2005)
looked specifically at the effects of rivastigmine on attention in PDD in patient enrolled in the Emre et al (2004)
trial. In this sub-study, 487 patients with PDD were given rivastigmine or placebo and assessed at baseline, 16 and 24-weeks. Assessment of attention on the Cognitive Drug Research (CDR) computerized assessment was performed at each visit in order to assess attention during various tasks. As compared with placebo, significant benefits on attention were noted among the rivastigmine group. Difficulty maintaining attention is a common finding in PDD and further asserts that rivastigmine is helpful for this impairment in these patients (Wesnes et al 2005
Economic evaluation of rivastigmine was examined soon after positive studies on PDD were published. Willan et al (2006)
prospectively examined the cost effectiveness of rivastigmine in the Emre et al (2004)
treated patients. Quality adjusted survival time (QAST) score was transformed from the MMSE score and utilized as a measure of cost effectiveness. Although an increase in QAST in the rivastigmine arm of 2.81 quality-adjusted life-days was noted (two-sided p-value 0.13 [90% CI –0.243, 5.86]), no between-treatment differences in cost were seen. The high variability in cost of medications (the study looked at Canadian and UK prices) as well as the short duration of the study (six months) could have interfered with the examination of cost effectiveness and further studies need to be performed.
Patients with PDD and DLB can often have autonomic nervous system dysfunction, and AChE can potentially increase acetylcholine and contribute to cardiac dysfunction. Ballard et al (2006)
reviewed cardiac safety of rivastigmine in DLB and PDD. Reviewing the Emre et al (2004)
PDD trial (n = 541) and the McKeith et al (2000)
DLB trial (n = 120), no clinically meaningful treatment differences in bradycardia or abnormalities on ECG were noted. Patients treated with rivastigmine did have a mean reduction of 1.5–2 beats per minute in heart rate, however. In fact, compared with placebo, it appears that rivastigmine was associated with fewer adverse events (p = 0.002) and fewer syncopal episodes (p = 0.018) among PDD patients (Ballard et al 2006