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Keywords:

  • cognitive impairment no dementia;
  • rivastigmine;
  • stroke

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. Author contributions
  10. References

Narasimhalu K, Effendy S, Sim CH, Lee JM, Chen I, Hia SB, Xue HL, Corrales MP, Chang HM, Wong MC, Chen CP, Tan EK. A randomized controlled trial of rivastigmine in patients with cognitive impairment no dementia because of cerebrovascular disease. Acta Neurol Scand: 2010: 121: 217–224. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard.

Objectives –  The safety and efficacy of early acetylcholinesterase inhibitors therapy in patients with cognitive impairment no dementia (CIND) after a cerebrovascular accident have not been examined. In this study, we investigated the safety and efficacy of rivastigmine in cognition, particularly executive function in patients with CIND because of cerebrovascular disease.

Methods –  This study was a 24-week, double-blind, randomized, placebo-controlled trial of ischemic stroke patients seen at a tertiary hospital who had cognitive impairment no dementia because of cerebrovascular disease. The intervention was either rivastigmine or placebo up to 9 mg/day. The primary outcome of interest was mean change from baseline in the Ten-Point Clock Drawing and Color Trails 1 and 2.

Results –  Fifty patients were randomized into rivastigmine (n = 25) and placebo (n = 25) arms. Patients in the rivastigmine group showed statistically significant improvement (1.70 vs 0.13, P = 0.02) on the animal subtask of the verbal fluency measure compared with placebo. There was also a trend (non-significant) towards improvement in Color Trails II.

Conclusions –  In this pilot study, we demonstrated that rivastigmine was well tolerated in patients with CIND because of cerebrovascular disease and may potentially improve executive functioning.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. Author contributions
  10. References

Dementia, mild cognitive impairment (MCI) and cognitive impairment no dementia (CIND) are frequently under-diagnosed and their incidence is likely to increase with an aging population. While there are no disease modifying treatments approved for dementia, the U.S. Food and Drug Administration has approved cholinesterase inhibitors (donepezil, galantamine and rivastigmine) for the symptomatic management of dementia in Alzheimer’s disease (AD). These drugs act to inhibit acetylcholinesterase, allowing levels of acetylcholine (a neurotransmitter that influences memory and learning) to increase, thereby improving cognition.

While cholinesterase inhibitors have been shown to improve cognition in trials involving demented AD patients (1), few have been evaluated in vascular dementia (2) and none have been evaluated in patients with CIND because of cerebrovascular disease (vascular CIND). In patients with vascular dementia, cholinesterase inhibitors have been found to improve scores on the Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog), neuropsychiatric inventory (NPI), and the activities of daily living (2). Patients with vascular CIND frequently have impairment of executive functioning while memory domains remain relatively intact (3). Vascular CIND has been shown to be associated with an increased risk of progression to dementia and recurrent vascular events (4, 5). Therefore, early identification of patients with vascular CIND, as well as intervention to improve or prevent deterioration of cognition could raise the quality of life of patients with vascular CIND.

Prompted by the current limited information on the early treatment of vascular CIND, we conducted a double-blind, placebo-controlled randomized study to evaluate the efficacy and safety of rivastigmine, a cholinesterase inhibitor, in patients with CIND because of cerebrovascular diseases. We hypothesized that patients receiving rivastigmine would improve on neuropsychological tests that assess executive functioning.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. Author contributions
  10. References

This study was an investigator-initiated, single center, double-blind, randomized placebo-controlled trial conducted at the Singapore General Hospital campus, National Neuroscience Institute between 20 February 2006 and 21 April 2007. The study protocol received ethics committee’s approval and all participants or their legally acceptable representatives provided written informed consent.

Participants

Participants were ischemic stroke patients aged 55–85 years, who had a neuropsychological evaluation (6), 3 months after their index stroke as part of their management at a tertiary hospital dementia was diagnosed according to DSM-IV criteria at weekly consensus conferences attended by neurologists, neuropsychologists, nurses and research assistants. Patients who were impaired in at least one cognitive domain but did not meet the criteria for dementia were considered to have CIND. Potential participants with CIND were evaluated using the inclusion and exclusion criteria. Patients also had vital signs measured, and underwent both a laboratory examination and an electrocardiogram. Neuroimaging that had been performed as standard clinical workup at the time of their index event was used to confirm that cerebrovascular disease was present. All patients received a magnetic resonance imaging (MRI) scan in which lesions with hypointensities in T1-weighted MRI and hyperintensities on T2-weighted MRI were verified as being consistent with a cerebrovascular event by neuroradiologists. Informed consent was collected at the beginning of the screening visit.

Of 154 patients with CIND who were screened, 50 patients were recruited and randomized into two groups: rivastigmine and placebo (Fig. 1). The 104 screen failures were caused by the following reasons: refusal (n = 69), health problems (n = 14), disability that prevented participation (n = 10), patient not being in Singapore (n = 4), possible dementia (n = 3), no caregiver (n = 3) and depression (n = 1). Fifty patients were randomized into this trial between 20 February and 20 November 2006. The study population was slightly older as compared with other CIND patients seen at the outpatient clinic at the hospital (mean age of 68.8 vs 65.3, P < 0.01), but was otherwise similar in terms of gender (66% vs 70% female), and ethnicity (70% vs 72% Chinese). Eligible patients were randomly assigned to one of the following two treatment groups: placebo or Exelon® (rivastigmine), up to 4.5 mg twice a day orally.

image

Figure 1.  Trial profile. AE, adverse event; SAE, significant adverse event.

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Exclusion criteria

Patients who were diagnosed with dementia were ineligible for this trial (Fig. 1). Other exclusion criteria included: (i) advanced, severe and unstable disease of any type that could interfere with the efficacy evaluations or put the subject at special risk; (ii) a current diagnosis of major depression according to the Diagnostic and Statistical Manual of Mental Disorders – 4th Edition (DSM-IV) (7) criteria; (iii) a disability that may prevent the subject from completing all study requirements (e.g. blindness, deafness, severe language difficulty); (iv) a known exaggerated pharmacological sensitivity or hypersensitivity to acetylcholinesterase inhibitors or to other cholinergic compounds; (v) ingestion of drugs that could interfere with the results of the trial in the preceding 4 weeks; and (vi) ingesting metrifonate in the preceding 3 months.

Neuropsychological evaluations

The neuropsychological test battery that was used in this study consisted of the Mini Mental State Examination (MMSE) (8), Ten-Point Clock Test (9), Color Trails Test 1 & 2 (10), ADAS-Cog (11), Cognitive Battery, Frontal Assessment Battery (12), AD Cooperative Study Activities of Daily Living (ADCS-ADL) (13) scale for MCI, NPI (14), and Geriatric Depression Scale (GDS) (15). These tests have previously been validated into six domains: attention, language, verbal memory, visual memory, visuoconstruction, and visuomotor speed.

Procedures

Randomization –  All eligible patients were given a randomization number that assigned them to either treatment or placebo. Randomization was performed in blocks of 4 using a randomization list that was produced by the pharmaceutical company’s supply management using a validated system that automates the random assignment of treatment groups to randomization numbers in the specified ratio. The randomization scheme was reviewed by a Biostatistics Quality Assurance Group and locked by them after approval. At randomization, all patients who fulfilled all the inclusion/exclusion criteria were given the lowest available number on the randomization list and received the first dose of 1.5 mg rivastigmine/placebo at baseline. A trial coordinator blind to the treatment allocation randomized each patient. The patient, psychologist, trial coordinator, clinicians and investigators were blinded to the treatment allocation.

Treatment –  Patients started treatment with 1.5 mg rivastigmine/placebo twice a day. After a 4-week minimum, the dose of rivastigmine/placebo was increased in patients who were able to tolerate the starting dose. To ensure parallel dose titrations, 3 dose levels were implemented with the following schedule: dose level 1.5 mg rivastigmine/placebo twice a day, dose level 3 mg rivastigmine/placebo twice a day and dose level 4.5 mg rivastigmine/placebo twice a day. Dose reductions were performed at any time during the titration period, while dose increases were done after a minimum 4-week period at the lower dose. There was complete flexibility in titrating doses, and a patient’s dose could be increased or decreased at any time throughout the rest of the study as determined by the investigator during the 24 week study duration.

Follow-up –  Patients were followed up every 4 weeks either by telephone or by visit to the clinic. At that time, information on any adverse reactions were collected. Any reported adverse reactions were cross referenced to hospital records.

Efficacy and safety outcomes

The primary outcome of the trial was to evaluate the comparative change from baseline on executive cognitive function in patients with CIND because of cerebrovascular disease, as measured by the Ten-Point Clock Test and Color Trails Test 1 & 2 in patients receiving 4.5 mg twice daily rivastigmine and placebo.

There were four secondary outcomes: to evaluate the comparative change from baseline on: (i) cognitive function, as measured by the ADAS-Cog and the neuropsychological test battery; (ii) activities of daily living as measured by the ADCS-ADL (MCI) questionnaire; (iii) depression as measured by the GDS; and (iv) behavior as measured by the NPI in patients receiving with 9 mg/day rivastigmine and placebo. Safety was assessed using adverse events, laboratory tests (renal and liver function tests), and vital signs (systolic and diastolic blood pressure).

Statistical analyses

Sample size calculations were based on data available from neuropsychological evaluations of stroke patients with CIND. Assuming a within group standard deviation of 3.5 for the clock drawing test and 70 for the Ten-Point Clock Test, a sample size of 49 (minimum of 25 treatment and 25 placebo) was required to detect a 2-point difference in the mean change from baseline on the Ten-Point Clock Test and a 40-s difference in the Color Trails tests with a power of 80% at an alpha of 0.05.

The safety evaluation analysis compared the means of laboratory tests and vital signs using a two-sample t-test statistic with a two-tailed alpha of 0.05. Fischer’s exact test was used to compare the proportions of patients who experience an adverse event (AE), a serious adverse event (SAE) or discontinue medication because of either an AE or SAE.

Efficacy was determined using a two-sample t-test statistic with a two-tailed alpha of 0.05 to test the difference in mean change between placebo and rivastigmine groups. Where imbalances at baseline were present, linear regression was used to adjust for baseline scores. All analyses were performed on Stata version 8.2 (16) in an intent-to-treat fashion. Reporting of this study was done in accordance with the CONSORT statement (17).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. Author contributions
  10. References

Follow-up was continued until the 21 April 2007. Emergency unblinding was not performed for any patient. One patient of age 48 years was erroneously randomized, but was allowed to continue in the trial as he was deemed to not be at an increased risk of AE or SAE. Of the 50 randomized, information on study outcomes was available for 49 patients (98%) as one patient in the placebo group died before a follow-up cognitive evaluation carried out at week 12.

Recruitment

Table 1 summarizes the demographic characteristics by treatment group. There was a significantly larger proportion of women (P = 0.04) in the rivastigmine arm as compared with the placebo arm. There were no significant differences in age, ethnicity or baseline MMSE between treatment and placebo arms.

Table 1.   Demographic characteristics of patient population stratified by treatment group
 Rivastigmine (n = 25)Placebo (n = 25) P-value
Gender, n (%)
 Male5 (20)12 (48)0.046
 Female20 (80)13 (52)
Ethnicity, n (%)
 Chinese20 (84)15 (60)0.186
 Malay2 (8)6 (24)
 Indian2 (8)4 (16)
 Other  
Age, mean (SD)68.1 (6.8)69.4 (9.1)0.625
Range57–8148–84
MMSE, mean (SD)23.7 (3.4)23.9 (3.2)0.566
Range16–2919–29

Efficacy

Data were unavailable for one patient (placebo) at both week 12 and week 24. Last observation was carried forward for three patients (two rivastigmine and one placebo) who had information at week 12 and not at week 24. These three patients had data unavailable at week 24 as two of them were too ill to be assessed at week 24 (pneumonia and acute myocardial infarction), and the third refused to complete the assessment. Table 2 summarizes the key efficacy results by treatment group (rivastigmine n = 25, placebo n = 24).

Table 2.   Mean and standard deviation (SD) of study population: Baseline and mean change from baseline stratified by treatment group
ItemsBaselineMean change from baseline to week 24
Rivastigmine Mean (SD)Placebo Mean (SD) P-valueRivastigmine Mean (5–95 percentile)Placebo Mean (5–95 percentile)P-value
  1. The items marked with R are coded in a reverse manner, i.e. the lower score, the better.

  2. ADCS-ADL, Alzheimer’s Disease Cooperative Study Activities of Daily Living; NPI, neuropsychiatric inventory; GDS, Geriatric Depression Scale; ADAS-Cog, Alzheimer’s Disease Assessment Scale Cognitive Subscale.

Primary outcomes
 Clock drawing6.2 (2.8)6.1 (3.3)0.790.1 (−0.8 to 1.0)0.5 (−0.2 to 1.4)0.39
 Color trails 1R (s)142.2 (64.1)167.2 (65.4)0.27−12.7 (−29.5 to 4.0)−21.4 (−45.9 to 2.5)0.53
 Color trails 2R (s)215.6 (41.8)218.1 (44.6)0.90−16.1 (−29.7 to −2.6)−0.6 (−18.9 to 9.5)0.09
Secondary outcomes
 ADCS-ADL59.6 (12.4)55.4 (9.3)0.473.2 (0.5 to 5.9)5.2 (1.2 to 9.8)0.37
 NPIR0.7 (1.4)2.3 (6.0)0.310.31 (−0.9 to 0.9)0.1 (−2.6 to 2.9)0.93
 GDSR3.0 (2.7)5.3 (4.5)0.03−1.0 (−2.0 to 0.4)−1.9 (−3.6 to −0.7)0.13
Cognitive battery
 Symbol digit modalities14.4 (10.4)10.9 (11.1)0.46−0.7 (−3.2 to 2.1)0.7 (−2.2 to 3.1)0.59
 Digit cancellation12.9 (5.9)14.2 (8.6)0.48−0.6 (−2.5 to 1.3)0.7 (−1.0 to 2.8)0.25
 MazeR (s)89.5 (80.4)94.9 (85.3)0.88−2.5 (−34.0 to 29.0)−30.6 (−63.7 to −2.2)0.16
 Verbal fluency animals9.0 (3.3)11.3 (2.8)0.011.7 (0.7 to 2.7)0.03 (−1.0 to 1.0)0.02
 Verbal fluency food11.1 (3.8)12.6 (4.4)0.160.3 (−1.0 to 1.5)1.2 (−0.8 to 2.7)0.50
 Visual memory (immediate)5.4 (1.7)6.0 (1.7)0.160.8 (0.3 to 1.4)0.7 (0.1 to 1.3)0.73
 Visual memory (delayed)4.6 (2.0)5.0 (2.0)0.360.8 (0.2 to 1.5)1.3 (0.8 to 1.8)0.27
 Visual memory (recognition)8.9 (1.3)9.1 (1.2)0.440.1 (−0.3 to 0.6)0.04 (−0.2 to 0.5)0.86
 Frontal assessment battery12.9 (2.7)13.1 (2.3)0.580.8 (−0.0 to 1.6)0.2 (−0.8 to 1.1)0.30
 ADAS-cogR29.9 (13.1)30.4 (14.1)0.92−0.6 (−3.1 to 1.9)−2.8 (−5.1 to 0.3)0.21

There were imbalances in the Verbal Fluency Animals subtest and GDS between the treatment and placebo arms at baseline, with patients in the placebo arm scoring higher on both tests (Table 2). As such, in addition to t-tests, linear regression analyses were performed on these subtests to correct for baseline imbalances.

Table 2 summarizes the efficacy results. There were no significant differences in mean change from baseline between rivastigmine and placebo in the primary endpoints of clock drawing and color trails tests. However, in color trails 2, there was a trend towards significant difference in mean change from baseline between rivastigmine and placebo (P = 0.09).

When comparing ADCS-ADL and NPI, there was no significant difference in mean change from baseline between rivastigmine and placebo. When comparing GDS, there was no significant difference in mean change from baseline between rivastigmine and placebo (P = 0.13). As GDS was imbalanced at baseline, additional linear regression analysis controlling for baseline GDS confirmed that there was no significant change from baseline (P = 0.12).

The ADAS-Cog and all items in the cognitive battery, with the exception of Verbal Fluency Animals, there was no significant difference from baseline. For the Verbal Fluency Animals item, the rivastigmine group improved significantly on the as compared with the placebo group (P = 0.02). As there was an imbalance at baseline, linear regression analysis controlling for baseline Verbal Fluency Animals score was used to further confirm the results (P = 0.01).

Safety

Tables 3 and 4 summarize the safety outcomes in this study. There were no significant differences between safety outcomes in placebo and rivastigmine arms. There was one death and five patients with SAEs each arm. Table 3 summarizes the clinically significant AEs experienced by nine patients in the rivastigmine group and 10 patients in the placebo group. One patient in the rivastigmine group and two patients in the placebo group discontinued their medication because of their SAE, while two patients in the rivastigmine group and three patients in the placebo group discontinued their medications because of their AE (Table 4). The SAEs reported in the rivastigmine group were TIA, anemia secondary to diabetic nephropathy, giddiness secondary to antihypertensive medication, focal motor seizures secondary to scar epilepsy, ponto-medullary infarct and congestive heart failure leading to death. The SAEs reported the in placebo group are junctional bradycardia secondary to digoxin toxicity, atypical chest pain, acute urinary retention secondary to constipation, death and pneumonia. All SAEs were deemed to have no relation to the study drug.

Table 3.   Number of patients with each adverse event (AE) by treatment group
 RivastigminePlaceboTotal
  1. *One AE that resulted in discontinuation of the treatment.

Total no. patients252550
No. (%)patients with AE(s)9 (36)10 (40)19
AE term, n (%)
 Nausea1 (4)*1 (2)
 Sleeping difficulties1 (4)1 (2)
 Headache1 (4)2 (8)3 (6)
 Gastrointestinal upset1 (4)1 (4)2 (4)
 Breathlessness1 (4)1 (4)2 (4)
 Giddiness/dizziness2 (8)2 (4)
 Diarrhea1 (4)1 (2)
 Vomiting3 (12)3 (6)
 Chest pain2 (8)*2 (4)
 Blurred vision1 (4)*1 (2)
 Fecal incontinence1 (4)*1 (2)
 Agitation with depression1 (4)*1 (2)
 Accidental fall1 (4)1 (2)
 Poor appetite1 (4)1 (2)
 Fracture of the left wrist1 (4)1 (2)
 Fracture of the left foot1 (4)1 (2)
Table 4.   Number of patients who died, had other serious or clinically significant adverse events (AE or SAE) or discontinued their medication because of them
 Rivastigmine n (%)Placebo n (%)
Death1 (4)1 (4)
SAE(s)5 (20)5 (20)
Discontinuation due to SAE(s)1 (4)2 (8)
AE(s)10 (40)11 (44)
Clinically significant AE(s)9 (36)10 (40)
Discontinuation due to clinically significant AE(s)2 (8)3 (12)

Systolic and diastolic blood pressure was measured at baseline, 4, 8 and 12 weeks. At baseline, the rivastigmine group had a significantly higher mean diastolic blood pressure than the placebo group (85.2 vs 79.0, P = 0.05). The diastolic blood pressure of the rivastigmine group subsequently decreased and at 4 weeks (80.9 vs 80.2, P = 0.86), 8 weeks (79.2 vs 77.9, P = 0.70), and 12 weeks (80.8 vs 81.6, P = 0.85), there were no differences in diastolic blood pressure between rivastigmine and placebo groups. There were no differences between the rivastigmine and placebo group in systolic blood pressure at baseline (140.6 vs 135.3, P = 0.33), 4 weeks (140.6 vs 139.5, P = 0.86), 8 weeks (134.2 vs 130.3, P = 0.39), and 12 weeks (137.6 vs 139.1, P = 0.83). One patient developed anemia secondary to diabetic nephropathy (rivastigmine) while no other patients had abnormal renal or liver function tests.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. Author contributions
  10. References

In this study, two primary endpoints, Ten-Point Clock Drawing and Color Trails Task, were used as surrogate markers for executive functioning and mean change from baseline was used to determine efficacy. In the Ten-Point Clock Drawing, we found no statistically significant difference between rivastigmine and placebo groups over the course of our study. There was a trend towards an improvement in the Color Trails Task (Trails 2), (absolute difference in mean change 15.5 s) for those receiving rivastigmine compared with placebo.

This study showed that treatment with rivastigmine does not increase the risk of having adverse events or significant adverse events when used in patients with CIND because of cerebrovascular disease. However, some patients did require a slower titration procedure than specified in the current protocol. As the patients in the placebo group were similarly unable to titrate up to the highest dose in accordance to the titration schedule in the protocol, we believe that this patient group with multiple co-morbidities were at a higher risk of experiencing AEs, and SAEs and therefore were more prone to deviate from the specified titration schedule. Future studies to examine the optimal titration dose (possibly over a longer time interval) would be useful. In trials examining the efficacy of rivastigmine (18–23) in patients with AD, patients have been titrated up to a varied dosage of between 1 and 12 mg/day.

Within the secondary outcomes, the animal subtask of the Verbal Fluency measure was the only item in which there was a statistically significant difference between rivastigmine and placebo treatment groups. The animal subtask, which is commonly used as a measure of executive functioning, improved significantly in patients receiving rivastigmine. We believe that dominant hand weakness, which could affect performance on the two primary endpoints, would not affect the animal subtask of the Verbal Fluency measure. Therefore, the animal subtask may provide a relatively unbiased estimate of the effect of rivastigmine on executive functioning. Future trials should therefore include the animal subtask or other such non-paper and pencil executive functioning tasks as a primary outcome measure.

It has been hypothesized that the disruption of cholinergic pathways by subcortical ischemic lesions is the mechanism of action by which cholinesterase inhibitors improves cognition in patients with vascular cognitive impairment (VCI). However, the utility of cholinesterase inhibitors in the treatment of VCI has yet to be established (24). In a recent trial examining the efficacy of donepezil on patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (25), patients receiving donepezil did significantly better on Trail Making Test A&B and on the executive interview-25 as compared with patients receiving placebo. However, their primary endpoint, the vascular AD assessment scale – cognitive subscale was not significantly different between donepezil and placebo groups. While this trial provides some evidence that cholinesterase inhibitors improve cognition in patients with VCI, there is yet no evidence that this improvement can be translated into improvements in clinical and functional endpoints.

Evidence from animal studies of cerebral blood flow and models of cerebral ischemia supports the use of cholinergic agents in the treatment of VCI (26). Besides vascular relaxation, the favorable outcome observed after cerebral ischemia in animals treated with rivastigmine may also be associated with improvement of impaired metabolism in the ischemic brain by suppression of energy demand and dissociation between the increase in CBF and metabolic activation, which may be of significant therapeutic importance.

We showed no significant difference in safety outcomes between those receiving rivastigmine and placebo. While rivastigmine has been approved for doses up to 12 mg daily, we chose a lower threshold of 9 mg/day as clinical observations have shown that loser doses may be more suitable in our Asian patients who tend to be smaller. However, a large majority of patients on rivastigmine and placebo alike had difficulty titrating up to a dose of 9 mg/day. Patients receiving rivastigmine treatment, who initially had a significantly higher mean diastolic blood pressure than the patients receiving placebo, were able to lower their diastolic blood pressure within a span of 4 weeks. In this study, CIND patients on rivastigmine did not have an increased risk of experiencing AEs, SAEs or changes in vital signs.

This study has some limitations. First, it is unclear whether the effect size difference between the two groups could be detected using the various neuropsychological tests at 24 weeks. It is also possible that unlike dementia patients, a longer period of treatment and follow-up would be needed to detect a greater improvement in CIND patients. Second, the patients involved in this trial were stroke patients who may have had weakness in the dominant hand. The choice of paper-and-pencil tasks as primary outcomes may therefore have biased results, as while cognitive functioning may improve, such an improvement may not necessarily translate into an improvement in test scores. We therefore recommend that more tasks measuring executive functioning be included in future trials. Some possible executive functioning tasks that can be included are the Stroop Test, Complex Figure Test, as well as Script Generation. Moreover, the use of the EXIT-25 or other computer-based executive functioning tests would eliminate any bias associated with dominant hand weakness. While we showed that rivastigmine was able to improve scores on the Verbal Fluency subtest, our results may be biased as a result of the baseline imbalances seen between rivastigmine and placebo in this subtest. Larger studies may be able to demonstrate this effect more robustly. Lastly, we were unable to control for any confounding related to stroke severity as we did not have functional motor scores for the strokes.

In conclusion, we demonstrate that Rivastigmine is well tolerated in patients with CIND because of cerebrovascular disease and may potentially improve executive functioning. This study findings provide impetus for larger longitudinal studies with a longer follow-up assessment should incorporate more tests of executive functioning to further evaluate the efficacy of cholinesterase inhibitors in the early treatment of CIND.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. Author contributions
  10. References

The trial was supported with an educational grant from Novartis, who has also supplied placebo-controlled study drugs and codes with randomization numbers. HLX is an employee of Novartis. All other authors report no conflicts of interest.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. Author contributions
  10. References

This work was supported by an educational grant from Novartis Pharma. The principal author takes full responsibility for the data, the analysis and interpretation, and the conduct of the research. The principal author also had full access to the data and has the right to publish any and all data separate and apart from the attitudes of the sponsor.

Author contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. Author contributions
  10. References

HLX, HMC, MCW and CPC were responsible for the design of the trial. SE, CHS, JML, IC, SBH, MPC, HMC, MCW and CPC were responsible for the collection of data. SE was responsible for the data cleaning. KN and SE were responsible for the statistical analyses. CPC, MCW, EKT rotated as PI and were responsible for the overall administrative, trial conduct and scientific supervision. KN, CPC and EKT were responsible for the drafting of the manuscript. All authors reviewed the manuscript and approved the final version. This trial is registered at clinicaltrials.gov (NCT00669344).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. Author contributions
  10. References
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