AD patients treated with galantamine in a routine clinical setting exhibited cognitive stabilization for up to one year after the onset of treatment. After three years of treatment, the mean MMSE change from baseline was 2.6 points. Subgroup response was assessed using cluster analyses, and two stable clusters were identified. Patients with higher age, lower cognitive and functional ability at baseline, faster pretreatment progression rate, and lower frequency of the APOE
4 allele exhibited a better short-term response to treatment, but dropped out earlier. Moreover, a high adherence to treatment was observed compared with that reported by earlier studies, and the three-year completers received higher galantamine doses than the noncompleters.
The routine clinical setting, which renders our results relevant also for the “ordinary” AD patient, was one of the advantages of the present study. This is especially important because the highly selected cohorts used in placebo-controlled trials may not be representative of patients in a real clinical setting.38
Moreover, even though we used a clinical routine setting, the data were collected prospectively and the evaluation was structured and standardized.
One of the limitations of long-term AD studies is the absence of a control group, which is not possible to obtain for ethical reasons. Because long-term, placebo-controlled studies in AD are limited in time to a duration of six months, the analysis of long-term outcome is limited to open-label studies. Because AD is a disease with a duration of decades, these open follow-up investigations are important.
The present study showed that mean MMSE levels in AD patients were improved over six months and were stable for up to one year after the onset of treatment. Stabilization over one year has been described previously in cohorts of galantamine-treated patients.39
The expected annual decline in MMSE score described previously was 2–4 points in nontreated historical cohorts32
and 2.2 points in placebo-treated patients.33
In the present study, the mean change in MMSE score from the baseline was 2.6 points, after not one but three years of treatment.
Moreover, the three-year deterioration in ADAS-cog score was 5.6 points compared with the one-year deterioration of 8 points described in older untreated AD cohorts30
and the 18-month deterioration of 6.7 points observed in a more recent study of a cohort with milder AD.40
The consistency between the outcomes obtained using two different scales strengthens these results. However, comparison of the outcomes of our study with those observed in previous placebo-controlled cohorts or earlier long-term studies must be performed with caution. Differences in cohorts, level of disease, and study design can influence the outcome. In an earlier analysis of Swedish Alzheimer Treatment Study data stemming from a donepezil-treated cohort, our group demonstrated a decline in MMSE score of 3.8 points after three years of treatment.21
Because that cohort was, on average, older and more cognitively impaired at treatment onset compared with the patients presented in the current study, the comparison of these results remains difficult, but will be obtained by our group in the future using statistical methods such as mixed models.
In the study presented here, 69% of the patients were globally assessed as “improved or unchanged” at one year, 50% were “improved or unchanged” at two years, and 41% were “improved or unchanged” at three years. This result was better than that observed in an earlier three-year follow-up study of donepezil-treated patients (49%, 35%, and 30%, respectively),21
as well as that observed in nontreated cohorts (34%, 13%, 14%, respectively).17
The response to ChEI treatment varies among the AD population. AD is a heterogeneous condition, and it is likely that the efficacy of various therapies differs among subgroups. This can depend not only on the medication used, but also on factors influencing disease progression (“how fast”) or disease severity (“how far”). Severity of disease and fast progression rate predict a positive short-term response to ChEI treatment in AD.41
However, the existence of malignant forms of AD with a fast progression rate and a lack of short-term response to ChEI treatment has also been reported.43
The definition of treatment response therefore remains difficult. There are no standard guidelines to describe response to treatment, and different definitions of response have been used previously.10
To overcome these difficulties in response definition, data-driven techniques, such as cluster analysis, may be better suited to the investigation of natural subgroups in AD treatment studies. Rockwood et al applied a cluster analysis to define outcome groups among a three-year completer population of AD patients.44
In the study presented here, we included not only the completer population, but all patients who provided at least six months of data. A stable two-cluster model was obtained, with different responses and characteristics. In our model, the response defined by the cluster analysis showed that patients exhibiting a better response at six months (cluster 1, n =76) had lower baseline ADAS-cog and IADL scores and a faster pretreatment progression rate, which was in line with earlier observations using other response definitions. The calculated estimation of pretreatment progression rate34
yielded the same predictive response (faster pretreatment progression/better short-term response) as that described in earlier cohorts for which pretreatment progression rate was measured, rather than being calculated.42
Analysis of the differences between dropouts and completers of the present study showed that the three-year completers had less advanced disease at baseline and received higher doses of galantamine than the noncompleters. Low doses of ChEIs have been associated with early discontinuation45
and some studies showed that higher ChEI doses enhance short-term response.46
These results stress the importance of using adequate ChEI doses in AD treatment to enhance adherence and response to treatment. Patients in cluster 2 dropped out to a lesser extent than patients in cluster 1. However, these two clusters did not differ in galantamine dose, but patients in cluster 2 were treated with lipid-lowering medication at baseline to a greater extent than patients in cluster 1. A protective effect of this medication cannot be ruled out, but this remains to be explored further using larger cohorts.
In our cohort, 27% of patients were medicated with antidepressants at baseline, ie, before inclusion in the study. This figure is not high in naturalistic cohorts, because several studies show that AD patients have a large comorbidity with depression, ranging from 20% to 30%. Among large European naturalistic AD cohorts, a 24% depression rate was described in one study47
and in another study anti-depressants were prescribed to 34% of the patients.48
We know that the patients receiving antidepressants at baseline did not drop out to a greater extent than the ones without this treatment.
High dropout rates are a problem in all long-term AD studies. Appendix 1
provides an overview of dropouts in various long-term studies to highlight this issue. Three-year completion rates of 4%–39% are reported. Thus, the three-year completion rate of 46% obtained in the current study is high compared with that of other long-term AD studies. In the present study, the two major reasons for dropout were addition of memantine or recruitment of patients to other treatment studies. As new treatment options emerged, patients were free to leave the present study to try other options. We do not know at this point whether these patients would have contributed to a different outcome if they had remained in the present study for the three-year period. We know that they were younger and better educated (data not shown), but did not differ in MMSE or ADAS-cog scores at baseline from the other dropout groups (data not shown). However, the possibility that patient deterioration was one of the reasons for adding memantine cannot be ruled out.
A recent observational health database study revealed that only 54% of patients receiving galantamine continued to do so for one year,49
which was longer than that observed for the donepezil-treated and rivastigmine-treated patients included in the same survey. Enhancement of the completion rates in long-term AD studies will be crucial in future studies of protective treatments, because these must be performed on a long-term basis.