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Response of Patients With Alzheimer Disease to Rivastigmine Treatment Is Predicted by the Rate of Disease Progression
Martin R. Farlow, MD;
Ann Hake, MD;
John Messina, PharmD;
Richard Hartman, PhD;
Jeffrey Veach, MS;
Ravi Anand, MD
Arch Neurol. 2001;58:417-422.
ABSTRACT
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Background Evidence suggests that disease severity predicts the response of patients
with Alzheimer disease (AD) to cholinesterase inhibitor treatment, raising
the question of whether disease progression also predicts response to this
treatment.
Objective To evaluate retrospectively whether rate of disease progression during
placebo treatment affects response to subsequent rivastigmine tartrate therapy
for patients with mild to moderately severe AD.
Design A 26-week, open-label extension study following a 26-week, double-blind,
randomized, placebo-controlled trial.
Setting Outpatient research centers at 22 sites in the United States.
Patients We studied 187 of 235 patients originally randomized to receive placebo
treatment in the double-blind phase of the trial who continued with open-label
(rivastigmine) extension therapy.
Intervention Placebo treatment for 26 weeks followed by rivastigmine treatment, 2
to 12 mg/d, for 26 weeks.
Main Outcome Measures Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS-Cog),
Progressive Deterioration Scale, Mini-Mental State Examination, and Global
Deterioration Scale scores.
Results Rivastigmine administration during open-label extension therapy benefited
patients who had progressed slowly and those who had progressed rapidly during
initial double-blind placebo treatment. Slowly progressive patients responded
with a mean 1.03-point improvement in the week 26 (ie, start of open-label
rivastigmine treatment) ADAS-Cog score at 12 weeks of rivastigmine treatment
(week 38 of treatment; P = .02 vs week 26). However,
more rapidly progressive patients had a significantly larger mean 4.97-point
improvement from the week 26 ADAS-Cog score at 12 weeks (with respect to week
26 of treatment and slowly progressive patient scores, P<.001 for both). Thus, a more rapid disease progression rate while
receiving placebo treatment was predictive of a significantly stronger patient
response to rivastigmine therapy. This relation also was observed with the
other 3 outcome measures and was still apparent when accounting for disease
severity.
Conclusions Rate of disease progression for patients with mild to moderate AD seems
to predict response to rivastigmine treatment. Patients with more rapidly
progressive disease might be particularly likely to benefit from rivastigmine
therapy.
INTRODUCTION
ALZHEIMER disease (AD), the most common form of dementia, affects up
to 6% of the US population older than 65 years1, 2
and is heterogeneous in its clinical presentation, including the rate of disease
progression. Investigators have described slowly progressive and rapidly progressive
forms of the disease,3, 4, 5
suggesting that there might be considerable variation in the disease process
or in the patient's vulnerability to the illness.
To determine prognosis for an illness such as AD, in which there is
a continuous neurodegenerative process, it is useful to assess how rapidly
the disease is progressing clinically and how severely the patient is currently
affected. The issue of which factor best predicts the course of AD—rate
of disease progression vs disease severity (ie, "how fast" vs "how far")—has
been the focus of much investigation.4, 6, 7, 8
Although rate of disease progression and disease severity seem to be predictive
of disease course, rate of progression might be more important than disease
severity in determining prognosis.9
Historically, AD severity was defined most often by the degree of cognitive
impairment.4 In this regard, instruments such
as the Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS-Cog)10 and the Mini-Mental State Examination (MMSE)11 were used to provide a measure of cognitive impairment.
However, it has been recognized that the degree of functional impairment also
reflects AD severity. The Global Deterioration Scale (GDS)12
was designed specifically to evaluate AD severity by measuring cognitive and
functional performance. In addition, scores on an instrument such as the Progressive
Deterioration Scale (PDS)13 also provide an
index of disease severity; they reflect the ability of the patient with AD
to perform specific instrumental and basic activities of daily living, which
become increasingly compromised as the disease progresses.
The inhibition of cholinesterase (ChE), the enzyme responsible for acetylcholine
catabolism, is the most extensively studied and best developed therapeutic
approach for the symptomatic treatment of AD, providing clinical benefit presumably
through an increase in synaptic acetylcholine levels and enhanced cholinergic
neurotransmission. Several attempts have been made to identify patient characteristics
that may best predict the level of response to ChE inhibitor treatment, including
disease severity, sex, and age. Substantial evidence suggests that patients
with AD in the moderate stage, during which disease progression is known to
be more rapid than during earlier stages, have a stronger response to ChE
inhibitor therapy than do patients with AD in the mild stage.14, 15, 16, 17, 18
This finding raises the question of whether rate of disease progression also
predicts treatment response.
Rivastigmine tartrate (ENA 713, Exelon; Novartis Pharmaceuticals Corp,
East Hanover, NJ) is a ChE inhibitor of the carbamate type that inhibits acetylcholinesterase
and butyrylcholinesterase and shows selectivity for the hippocampus and cortex,
regions in which cholinergic deficits are most prominent in AD.19
In a 26-week study of rivastigmine treatment efficacy and safety in patients
with AD (study B352, Novartis Pharmaceuticals Corp),20
patients were randomized to receive either rivastigmine or placebo treatment.
Following 26 weeks of double-blind treatment, patients had the opportunity
to continue into a 26-week open-label treatment phase (study B353, Novartis
Pharmaceuticals Corp). These sequential trials have allowed for evaluation
of patients initially treated for 26 weeks with placebo, who may have declined
at a slower or faster rate during this period, and subsequently treated with
rivastigmine for 26 weeks.
The objective of this study was to analyze retrospectively the data
obtained from the 2 sequential rivastigmine trials (double-blind study B352
and open-label study B353) to evaluate the relation between the underlying
rate of disease progression for patients with mild to moderately severe AD
and the response to rivastigmine treatment.
PATIENTS AND METHODS
STUDY DESIGN AND PATIENTS
This was a 26-week, open-label extension study following a 26-week,
double-blind, randomized, placebo-controlled, parallel group trial of 2 dose
levels of rivastigmine for treatment of patients with mild to moderately severe
AD.
Patients were enrolled in the double-blind study according to inclusion
and exclusion criteria described previously.20
These patients had the option to continue into the open-label extension study
if they had returned for scheduled efficacy evaluations at week 26 of the
double-blind trial. Of 235 patients originally enrolled in the 26-week double-blind
study and randomized to receive placebo treatment, 187 (80%) continued into
the 26-week open-label extension study and are the subject of this retrospective
analysis. All procedures were performed in accordance with the ethical standards
of the institutional committees on human experimentation and with the Helsinki
Declaration of 1975 as revised in 1983.
RIVASTIGMINE TREATMENT
During open-label treatment with rivastigmine, investigators and patients
remained masked to the patient's original treatment assignment (ie, placebo
or 1 of 2 dose levels of rivastigmine) in the preceding double-blind trial.
The morning after the last office visit of the double-blind trial, patients
began open-label rivastigmine (1 mg twice daily) treatment and had their dose
flexibly titrated (at a rate of 1 mg twice daily per week) to a maximum tolerated
dose of up to 6 mg twice daily.
ASSESSMENTS OF TREATMENT RESPONSE
Patient response to open-label rivastigmine treatment was evaluated
using 4 instruments that assessed patient cognition, function in performing
activities of daily living, and disease severity. The ADAS-Cog is a 70-point
scale used to assess patient cognition.10 A
higher score represents poorer cognitive performance, and a negative change
from the baseline score with treatment reflects improvement; ADAS-Cog scores
were evaluated at week 26 (ie, the start of open-label treatment) and at weeks
38, 44, and 52 of treatment or at early termination.
The PDS, an evaluation of performance of basic and instrumental activities
of daily living, is a 100-point bipolar visual analogue scale that, based
on caregiver input, measures the ability of patients to perform various activities
of differing complexity.13 A higher score represents
better functional ability, and a positive change from the baseline score reflects
an improvement; PDS scores were evaluated at week 26 (ie, the start of open-label
treatment) and at weeks 38, 44, and 52 of treatment or at early termination.
The MMSE and the GDS were used to stage the severity of the disease.
The MMSE is a 30-point scale that measures the severity of cognitive impairment,
with a score of 30 representing "normal" cognitive performance.11
The GDS is a 7-point scale that measures the degree of impairment in cognitive
performance, self-care activities, and the ability to perform activities of
daily living, with a score of 7 representing severe cognitive impairment12; MMSE and GDS scores were evaluated at week 26 (ie,
the start of open-label treatment) and at week 52 of treatment or at early
termination.
STATISTICAL ANALYSES
Retrospective analyses of these data were based on the observed population,
which included all patients taking the drug who were evaluated at the designated
times.
In assessing the relation between rate of progression and treatment
response, 2 types of analyses were performed. First, patients were classified
with respect to disease progression as being "slow" vs "rapid" based on the
magnitude of change seen during 26-week double-blind placebo treatment. Patients
were classified separately with respect to change in their ADAS-Cog and PDS
scores.
The ADAS-Cog and PDS scores were chosen as the basis for progression
classification because they measure cognitive and functional changes, respectively,
with both of these domains having been used in the past to measure disease
progression. Untreated patients decline at an average annual rate of approximately
6 to 12 points on the ADAS-Cog.21 Moreover,
a 4-point change in the ADAS-Cog score and a 10% change in the PDS score are
considered clinically meaningful.22 In this
regard, slow progression was defined as less than a 4-point deterioration
on the ADAS-Cog and, separately, less than a 10% worsening on the PDS during
the initial double-blind 26-week trial. Rapid progression was defined as at
least a 4-point deterioration on the ADAS-Cog and, separately, at least a
10% worsening on the PDS during this same period. These 2 groups of patients
were compared using an analysis of variance model. This model was fit with
(2-way model with progression and sex as factors) and without (1-way model
with progression as a factor) covariates for age and baseline score. The 2-way
analysis of covariance was performed to assess the robustness of any effect
after adjusting for sex, age, and baseline score. Simple linear regression
models also were fit to assess the linear relation between the "change from
baseline score at the end of 26-week placebo treatment" and the "change from
week 26 assessment score." In addition, multiple linear regression was used
to assess the effect of the change from baseline score at the end of 26-week
placebo treatment in the presence of baseline disease severity.
For all analyses, nominal P<.05 determined
statistical significance.
RESULTS
PATIENTS
The demographic and baseline characteristics of the evaluated patients
are summarized in Table 1. Patients
categorized as being slowly or rapidly progressive based on less than a 4-point
or a greater than or equal to a 4-point deterioration in the ADAS-Cog score,
respectively, were comparable in age, distribution according to race and sex,
and mean dementia duration. Similarly, categorization of patients as slowly
or rapidly progressive based on less than a 10% or an equal to or greater
than 10% deterioration in the PDS score, respectively, also did not reveal
any substantial differences between the demographic characteristics of these
patient groups.
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Table 1. Demographic and Baseline Characteristics of Patients*
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Sixty-five percent of patients progressed to taking a mean rivastigmine
dose of 6 to 12 mg/d during open-label treatment.
Of 187 patients enrolled in this open-label extension study, an average
(based on the 2 outcome measures used to categorize rate of disease progression)
of 26.5% of slowly progressive patients and 24.0% of rapidly progressive patients
discontinued rivastigmine treatment. The most common reason for treatment
discontinuation was the emergence of adverse events. On average, approximately
15.5% of patients with slowly progressive disease and 10.0% with rapidly progressive
disease discontinued study participation because of adverse events. Other
reasons for study discontinuation included consent withdrawal (slowly progressive
patients, 7.0%; rapidly progressive patients, 5.5%), treatment failure (slowly
progressive patients, 0.0%; rapidly progressive patients, 4.0%), failure to
return for office visits (slowly progressive patients, 2.0%; rapidly progressive
patients, 1.0%), and other reasons (slowly progressive patients, 2.0%; rapidly
progressive patients, 3.5%).
Almost all patients, regardless of rate of disease progression and rivastigmine
dose used, experienced at least 1 adverse event during the study. Of patients
considered to be slowly progressive, an average (based on the 2 outcome measures
used to categorize rate of disease progression) of 96.5% receiving rivastigmine,
6 to 12 mg/d, and an average of 88% receiving less than 6 mg/d experienced
at least one adverse event during the study. Similarly, of patients considered
to be rapidly progressive, an average of 95.5% receiving rivastigmine, 6 to
12 mg/d, and an average of 94% receiving less than 6 mg/d experienced at least
1 adverse event. In general, for slowly and rapidly progressive patients,
a greater proportion receiving rivastigmine, 6 to 12 mg/d, than receiving
less than 6 mg/d tended to experience adverse events (data not shown). However,
this was not observed consistently across all body systems assessed or all
specific adverse events recorded. The inconsistency of observations across
body systems and specific adverse events, together with small sample sizes
(n 14) in the less than 6 mg/d groups complicated any interpretation of
a dose–adverse response relation. For slowly and rapidly progressive
patients, the most frequently occurring adverse events were gastrointestinal
in nature (data not shown).
RATE OF DISEASE PROGRESSION AND RESPONSE TO RIVASTIGMINE TREATMENT
Assessment Using the ADAS-Cog
Responses to rivastigmine treatment as measured by the ADAS-Cog during
weeks 26 to 52 for patients classified as slowly or rapidly progressive based
on the change in ADAS-Cog score are depicted in Figure 1. Slowly progressive patients had a week 26 ADAS-Cog score
that was significantly better than the week 26 ADAS-Cog score of rapidly progressive
patients (17.5 vs 33.5; P<.001). Patients classified
as being rapidly progressive exhibited a marked improvement from week 26,
with a mean change of 4.97 points (P<.001) after
12 weeks of treatment (week 38 of study participation), a response that was
significantly better than that observed for slowly progressive patients (P<.001). At subsequent points, ADAS-Cog scores for rapidly
progressive patients declined but continued to show significant improvement
from the week 26 value and remained significantly better than the scores for
slowly progressive patients (Figure 1).
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Figure 1. Response of patients with Alzheimer
disease to rivastigmine treatment based on their rate of disease progression
as defined by the degree of deterioration in the Alzheimer's Disease Assessment
Scale–cognitive subscale (ADAS-Cog) score. Slowly progressive patients
were defined by less than a 4-point deterioration in ADAS-Cog score during
the preceding 26 weeks of placebo treatment. Rapidly progressive patients
were defined by a 4-point or greater worsening in ADAS-Cog score during the
preceding 26 weeks of placebo treatment. Sample sizes and mean ± SE
changes from the week 26 score were as follows: rapidly progressive patients—week
38: n = 71, 4.97 ± 0.83; week 44: n = 68, 2.57 ± 0.79; and week
52: n = 65, 2.01 ± 0.97; and slowly progressive patients—week
38: n = 86, 1.03 ± 0.44; week 44: n = 82, -0.57 ± 0.50;
and week 52: n = 78, -0.90 ± 0.57). Asterisk indicates P<.05 compared with the week 26 (ie, the start of rivastigmine treatment)
score; dagger, P<.05 compared with slowly progressive patients.
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Assessment Using the PDS
Responses of patients classified as slowly or rapidly progressive based
on change in PDS score were evaluated according to performance on the PDS
(Figure 2). Slowly progressive patients
had a week 26 PDS score that was significantly better than the week 26 score
of rapidly progressive patients (61.0 vs 38.5; P<.001).
Rapidly progressive patients showed little change from the week 26 PDS score
during the study, whereas slowly progressive patients showed a significant
worsening from the week 26 score at weeks 38, 44, and 52. Patients classified
as rapidly progressive had significantly stronger responses to treatment than
did slowly progressive patients at weeks 38 and 44 (Figure 2).
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Figure 2. Response of patients with Alzheimer
disease to rivastigmine treatment based on their rate of disease progression
as defined by the degree of deterioration in the Progressive Deterioration
Scale (PDS) score. Slowly progressive patients were defined by less than a
10% worsening in PDS score during the preceding 26 weeks of placebo treatment.
Rapidly progressive patients were defined by at least a 10% or greater deterioration
in PDS score during the preceding 26 weeks of placebo treatment. Sample sizes
and mean ± SE changes from the week 26 score were as follows: rapidly
progressive patients—week 38: n = 63, 0.07 ± 1.06; week 44: n
= 62, -0.29 ± 1.06; and week 52: n = 59, 0.34 ± 1.31;
and slowly progressive patients—week 38: n = 86, -2.74 ±
0.72; week 44: n = 80, -3.87 ± 0.85; and week 52: n = 78, -2.54
± 0.88). Asterisk indicates P<.05 compared with the
week 26 (ie, the start of rivastigmine treatment) score; dagger, P<.05
compared with slowly progressive patients.
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Simple Linear Regression Analyses of the ADAS-Cog and PDS Data
Results of linear regression analyses for weeks 38, 44, and 52 of treatment
are summarized in Table 2. There
was a statistically significant inverse relation between the magnitude of
patient response to rivastigmine treatment and disease progression that was
observed regardless of whether disease progression was defined by the rate
of deterioration in ADAS-Cog score or by the rate of deterioration in PDS
score.
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Table 2. Linear Regression Analyses of Change From Week 26 Assessment
Scores With Rivastigmine Treatment as a Function of Degree of Deterioration
in These Scores After Placebo Treatment
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Covariate and Multiple Linear Regression Analyses
Additional covariate analyses were performed to determine the effect,
if any, of baseline assessment scores (ie, disease severity), sex, and age
on the relation between patient response to rivastigmine treatment and rate
of disease progression. Results of the ADAS-Cog and PDS covariate analyses
were consistent with each other and showed that the relation between response
to rivastigmine treatment and rate of disease progression was consistent with
previous analyses that did not include baseline severity, sex, and age in
the model.
Similarly, when the covariate analyses also included an adjustment for
mean rivastigmine dose, response patterns similar to those described previously
and presented in Figure 1 and Figure 2 were observed over time for the
ADAS-Cog and PDS scores, respectively (data not shown). Moreover, the relation
between response to rivastigmine treatment and rate of disease progression
remained statistically significant for these 2 treatment assessments (data
not shown).
Multiple linear regression models showed that even after baseline disease
severity was accounted for, change from baseline score at the end of 26 weeks
of placebo treatment still significantly predicted magnitude of response to
rivastigmine therapy (Table 2).
Assessments Using the MMSE and the GDS
Results of linear regression analyses using data derived from MMSE or
GDS assessments were consistent with those obtained from analyses of the ADAS-Cog
and PDS data. For the MMSE and the GDS, there was a statistically significant
inverse relation between the response to 26 weeks of rivastigmine treatment
and the degree of deterioration in the particular assessment score after placebo
treatment (Table 2).
COMMENT
The present retrospective analyses show that the magnitude of patient
response to rivastigmine treatment may be predicted, at least in part, by
the rate of disease progression preceding treatment. Patients with more rapid
rates of disease progression manifested a significantly stronger response
to rivastigmine treatment than did patients with a slower rate of disease
progression. To our knowledge, this is the first study of a relation between
patient response to ChE inhibitor treatment and rate of disease progression.
The relation between response to rivastigmine treatment and rate of
disease progression was evaluated using 4 different assessments of patient
response (ADAS-Cog, PDS, MMSE, and GDS) and 2 different statistical models
(using progression as a categorical and linear predictor of response). A statistically
significant inverse relation between response to rivastigmine treatment and
rate of disease progression, in which a greater treatment response was predicted
by a more rapid rate of disease progression, was consistently observed in
all 4 assessments of treatment response. Furthermore, results of the analysis
of variance and linear regression analyses (performed for ADAS-Cog and PDS
assessments) were consistent. In addition, when disease severity, as defined
by baseline assessment score, was accounted for in the covariate and multiple
regression analyses, the relation between response to rivastigmine treatment
and rate of disease progression remained statistically significant. Collectively,
these findings constitute highly compelling evidence of a relation between
the magnitude of the response to rivastigmine treatment and the rate of disease
progression.
That the rate of disease progression before treatment seems to be a
strong and selective predictor of response to ChE inhibitor therapy is reflected
most dramatically by the ADAS-Cog data from this study. After 12 weeks of
treatment with rivastigmine, patients classified as rapidly progressive demonstrated
a 4.97-point improvement in ADAS-Cog score relative to the mean score at week
26.
It has been proposed that the rate of disease progression (ie, how fast),
as measured by the rate of cognitive9 or functional
decline, may be more important than disease severity (ie, how far) for predicting
disease course and the time to certain end points such as nursing home placement
or death. Data from the present analyses suggest that rate of disease progression
may be valuable not only for establishing a prognosis but also for predicting
the level of responsiveness of patients with AD to rivastigmine treatment
and, possibly, to therapy with other ChE inhibitors.
Why some patients with AD decline more rapidly than others is not currently
known. Several factors have been suggested to impact the rate of disease progression,
including apolipoprotein E genotype,23 the
early appearance of aphasia or apraxia,24 the
presence of extrapyramidal signs25 or certain
behavioral symptoms,26 and genetic factors.3 However, the relation of these factors to the underlying
pathophysiologic features and processes of the disease remains unclear. The
rate of decline might reflect the cumulative effects of different neuropathologic
processes, including cholinergic cell loss, that may spread at widely differing
rates in individual patients.
In summary, rivastigmine may have greater treatment effects in patients
with more rapidly progressive disease. The relation between response to rivastigmine
treatment and rate of disease progression was still apparent when accounting
for disease severity. Whether patients with more rapidly progressive AD are
more responsive to treatment with other ChE inhibitors or alternative interventional
therapies remains to be determined and merits investigation in future studies.
AUTHOR INFORMATION
Accepted for publication July 31, 2000.
This study was supported by grant P30 AG10133-08 from the National Institutes
of Health, Bethesda, Md (Dr Farlow).
We acknowledge the patients and clinical investigators who participated
in this study.
From the Department of Neurology, Indiana University School of Medicine,
Indianapolis (Drs Farlow and Hake); and Novartis Pharmaceuticals Corp, East
Hanover, NJ (Drs Messina, Hartman, and Anand and Mr Veach). Dr Farlow has
acted as a consultant to, or been provided research support by, Novartis Pharmaceuticals
Corp, the sponsor of study B353, from which the data presented herein were
derived.
Corresponding author and reprints: Martin R. Farlow, MD, Department
of Neurology, Indiana University School of Medicine, CL583, 541 Clinical Dr,
Indianapolis, IN 46202-5111 (e-mail: mfarlow{at}iupui.edu).
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