Tacrine

Keywords: Alzheimer's disease, clinical trials, meta-analysis, systematic review, tacrine

Introduction

Alzheimer's disease (AD) ranks among the principal public health problems confronting developed countries [1, 2]. Cholinergic deficiency is one of the main defects found in the brains of such patients and correlates with poor performance in cognitive tests [3, 4], although other mediators of neurotransmission have also been linked to AD physiopathology [5-10]. This finding led to the hypothesis that enhancing the cholinergic function of the central nervous system could slow the mental deterioration associated with the disease [12, 13]. An initial AD treatment strategy was thus based on administration of choline, but clinical studies failed to demonstrate its efficacy [14]. This was followed by studies of muscarinic agonists, such as bethanechol, arecoline and oxotremorine, but adverse effects and low selectivity for the central nervous system limited their clinical use [15]. Lastly, cholinesterase inhibitors were used in order to augment the availability of acetylcholine in neuron receptors. Among these drugs is tacrine (tetrahydroaminoacridine). This aminoacridine acts on the central nervous system in a manner that is both complex and diverse: its known pharmacological actions include longer lasting cholinesterase inhibition than physostigmine and restoration of nicotinic receptors in AD-affected brains [16-19].

Reviews of clinical trials help obtain clear scientific evidence on the benefits, risks and costs of any given therapeutic intervention and are a tool of evidence-based medicine [20]. Narrative reviews have been published describing trials of drugs, including tacrine, for the treatment of AD [21-29]. The chief advantages of systematic as opposed to narrative reviews are the lower probability and magnitude of biases along with greater repeatability [30, 31]. Accordingly, the aim of this study is to review systematically the methodological characteristics, results and quality of trials of tacrine in the treatment of AD.

Materials and methods

Study-inclusion criteria

Trials included were those conducted on AD patients, aged 40 years or over, assigned to tacrine- or placebo-based treatment. Trial participants were selected on the basis of the degree of probability of the diagnosis of AD, as indicated by National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria [32], and the degree of severity, as indicated by Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-III-R) criteria [33]. Information on tacrine efficacy was rated by one of the following types of scales: cognitive function, behavioural, functional ability, global impression of clinical change and global scales of mental deterioration.

Study-search strategy

Studies were identified in the following electronic databases: the Cochrane Library (which includes the Cochrane Database of Systematic Reviews, the Cochrane Controlled Trials Register, the Cochrane Review Methodology Database and the York Database of Abstracts of Reviews of Effectiveness) and MEDLINE, for the period 1 January 1980-1 May 1997, using the search strategy proposed by Dickersin et al. [34].

Extraction and presentation of data

Selection of trials for systematic review and data extraction purposes was carried out separately by two reviewers (J.L.A. and F.R.A.) working independently. Where differences of opinion arose, these were resolved by discussion between the two. Study reporting quality was assessed according to guidelines laid down by the Standards of Reporting Trials Group [35]. These guidelines list the information to be provided in the publication of a random clinical trial and are useful for evaluating the quality of the reporting but not that of the study per se. Overall scores were obtained by totalling the points for 32 items, grouped within the following areas: description of the allocation of participants to each treatment; description of the blinding of the intervention and whether this proved successful; description of subject follow-up and possible losses to follow-up; and description of the statistical analysis in the Methods and Results sections of the paper. The presence of each piece of information is awarded a score of 1, and its absence 0, so the maximum possible score for any paper is 32. Total scores for the paper and subscores for each of its sections are provided as absolutes and as a percentage of the possible maximum. Due to the heterogeneity of trial methods and the low number of studies published, no statistical synthesis of study results has been drawn up.

Results

We located 49 publications on the efficacy of tacrine in the treatment of AD, published in the period 1981-1996 [36-84]. Of these, one was a summary of a communication delivered to a congress [74], three were chapters of a book [39, 40, 45] and the remainder were papers included in MEDLINE.

Of the 49 publications, 22 corresponded to non-randomized and/or open clinical trials and the remaining 27 reported 18 double-blind, randomized clinical trials. To identify the most appropriate tacrine dosage, three of the 18 random trials included titration phases with randomized, double-blind, treatment allocation. These trials--reported by Forette et al [74-75], by Davis et al. [76-77] and Foster et al. [84]--were therefore deemed to be studies in their own right, independent of the main study, thereby bringing the figure of random trials in this review to 21.

The methodological characteristics and results of the 22 non-randomized and/or open trials are summarized in Table 1. The first trials were notable for their smaller sample size and the fact that tacrine-treatment dosage and duration were variable, ranging from single doses to 9 weeks of treatment. 1990 signalled the commencement of longer studies. The follow-up phases of random trials of tacrine were found among these studies, which also included mortality or degree of institutionalization as outcome variables [57]. All trials used psychometric instruments to rate patients' mental function. Furthermore, in six trials, brain function techniques--positron emission tomography and single photon computed tomography imaging [48-50, 52, 55, 56]--were employed, in four trials the electroencephalographic register was studied [44-47] and in two, indirect methods were used to evaluate the cholinergic effect of tacrine [43, 51]. In seven studies, lecithin was associated with tacrine [37, 39, 41, 42, 46-48]. In all the open studies there was improvement in some of the variables measured; only in the studies conducted by Summers et al. [36], Kaye et al. [37], Gauthier et al. [39, 41], Alhainen et al. [43] and Knopman et al. [57] did such improvement attain statistical significance, although, on occasion, discontinuation of tacrine led to a reversal to the baseline situation [39, 41]. In seven trials, adverse events were described for almost 60% (19-80%) of subjects treated with tacrine [36, 38-42, 54].

[TABULAR DATA 1 NOT REPRODUCIBLE IN ASCII]

Table 2 summarizes the design, treatment characteristics and patient-enrolment criteria in the 21 random clinical trials of tacrine in AD. Of these, eight were parallel and 13 cross-over in design. Tacrine dosage ranged from 25 to 200 mg/day. Duration of treatment ranged from 3 to 36 weeks, with a mean [+ or -] standard deviation of 9.3 [+ or -] 8.6 weeks (6.53 [+ or -] 3.8 weeks in the cross-over and 13.9 [+ or -] 12.3 weeks in the parallel random trials). Only two studies [78, 82] used a pre-established tacrine dosage; the remaining trials included a preliminary titration phase. Mean age of participants was 68.9 years: 67.6 years in the cross-over studies and 70.7 years in the parallel-group random trials. In 17 random trials, NINCDS-ADRDA criteria were used for diagnosis of AD among participants and in seven random trials DSM-III-R criteria were used to assess severity of mental deterioration. Subject enrolment was based on diagnosis of probable AD of mild to moderate severity.

[TABULAR DATA 2 NOT REPRODUCIBLE IN ASCII]

In all, 3555 patients were enrolled. Parallel-group random trials had a larger sample size, with 2244 patients enrolled versus 1424 in the cross-over random trials (Table 2). A total of 1149 subjects failed to complete the trial, yielding a mean of 33.4% patients per trial. Of these, 1116 (97%) patients received treatment with tacrine. Adverse events, generally in the form of cholinergic manifestations (digestive symptoms, sweating) or serum transaminase elevations exceeding three times the upper limit of normal, appeared in 59.3% of individuals; 30.2% suffered some type of cholinergic symptom and 28.6% showed hepatotoxicity (Table 3). Adverse events were the chief reason for patient withdrawal.

[TABULAR DATA 3 NOT REPRODUCIBLE IN ASCII]

The 21 random trials employed 157 outcome variables, with 3-31 used per trial, except for the Forette et al. [74-75] and Davis et al. [74, 75] titration phases where only the Mini-Mental State Examination (MMSE) [85] was used. Among the instruments used for studying intellectual functions, the MMSE proved to be the most frequent (Table 4). Of the behavioural scales, the most common was the Alzheimer's Disease Assessment Scale (ADAS) non cognitive subscale [86]. The most widely used functional scales were Lawton's [87, 88], particularly the instrumental activities of daily living scale and physical self-maintenance scale. General impression tests were used to grade assessor-based subjective aspect of improvement, with the clinician's global impression of change [89] being most in evidence. The global scale of intellectual deterioration most widely favoured was the total score yielded by Al)AS [86] rating (Table 4). Only seven studies [69-73, 74-75, 78, 80, 82-84] specified the primary and secondary assessment variables at the outset of the trial.

ADAS, Alzheimer's disease assessment scale; MMSE, mini-mental state examination; WMS, Wechsler memory scale.

The results on tacrine efficacy in the 21 random trials are summarized in Table 5. In 12 trials, tacrine produced statistically significant improvement (P [is less than] 0.05) in one or more outcome variable, in five trials the drug led to non-significant improvement and in the remainder scarcely any difference was found between tacrine and placebo. The improvement was in cognitive variables in 12 instances and it was in overall ratings in seven. Instruments of functional ability and global clinical impression ratings showed improvements in three trials each and in only one case did tacrine show efficacy in a behavioural scale. Bearing in mind that of the subjects exposed to tacrine, 24.4% discontinued the treatment and 50.2% manifested adverse effects which generally forced them to reduce the dosage, only a little over 20% of patients initially treated with tacrine achieved some clinical benefit as against the placebo.

[TABULAR DATA 5 NOT REPRODUCIBLE IN ASCII]

In line with Schneider's classification [20], random trials were divided according to sample size into small [58-61, 64-68, 79] (having under 50 participants) and large [62, 63, 69-78, 80-84] (having over 50 participants). The seven small trials were carried out earlier and all but one had a cross-over design. Of the seven, tour showed some significant difference (P [is less than] 0.05) in favour of tacrine and three yielded negative results. Of the large-scale trials, half were parallel and all were carried out more recently. The results in 12 of these 14 showed clinical improvements attributable to tacrine.

The reporting quality of the 21 random trials is shown in Table 6. No study gave a description of the concealment of the randomization sequence or the success of the double-blind procedure. Over 50% of the relevant information was reported only for the following areas: coverage of follow-up and statistical analyses in the Results section of the paper (Table 6). Cross-over random trials supplied 30.7% and parallel-group random trials 40.2% of all relevant information. The study with the best reporting quality was that by Knapp et al. [82], which supplied 50% of the relevant information.

Table 6. Reporting quality of randomized clinical trials of tacrine in Alzheimer's disease

(a) Percentage of the maximum possible score: assessment as per Guidelines of the Standards of Reporting Trials Group (1994) [35].

Discussion

This systematic review has pinpointed three stages in clinical research on tacrine in AD. The first stage comprises trials conducted in the 1980s and early 1990s, with small sample sizes, non-randomized and/or open designs and relatively small doses of tacrine over short periods of time [36-45] (Table 1). These studies generated excessively optimistic expectations as to the benefits of tacrine. Their chief contribution was to demonstrate the hepatotoxic effects of tacrine, even at low doses, and to stimulate research in this field.

The second stage was of trials that were more methodologically sound, characterized by randomized allocation of treatment and conducted in the second half of the 1980s and in the 1990s (Tables 2-6) [58-84]. The considerable number of scales used in the random trials in order to rate response to treatment (Table 4) suggests that none proved altogether satisfactory [90]. Moreover, there are serious shortcomings in the reporting of the results of these studies. Particularly noteworthy is the lack of information on the concealment of the randomization sequence and the success of the double-blind procedure, since there is empirical evidence to show that this can spuriously magnify the effect estimators [91, 92].

Among these `second-stage' random trials, the most informative are those by Farlow et al. [78] and Knapp et al. [82], together with the comparative double-blind phases of the studies by Forette et al. [74, 75] and Davis et al. [76, 77]. These studies have a large sample size, thereby enabling more precise measurement of the effect of tacrine, and a parallel design, which makes it possible to control for time-dependent confounders. This is important as the clinical course of Al) varies widely, with periods of cognitive stabilization of up to 2 years [93]. Inclusion criteria are clear (DSM-III-R and NINCDS-ADRDA), affording relative assurance on the diagnosis and homogeneity of patients studied. In most cases the ADAS scale was used as the principal variable of assessment, this scale being one of the most reliable having been drawn up to evaluate the therapeutic effects of drugs in AD [94]. Furthermore, these studies report the relationship between tacrine dosage and the drug's efficacy and toxicity. Finally, they earned some of the highest ratings for reporting quality (Table 6).

The third stage takes in studies that provided continued follow-up for some `second-stage' random trials and were carried out in the period 1993-96 [52-57] (Table 1). They supply information on the long-term effects (safety) of tacrine and, in certain cases, on its effect t)n the quality of life, institutionalization and mortality of AD patients [57]. The chief limitation on these studies lies in their lack of a control group (ideally composed of untreated AD patients), with the result that they have a limited capacity for drawing inferences on clinical usefulness.

`Second-stage' random trials have shown that tacrine has a modest dose-dependent efficacy in cases of mild to moderate AD. The greatest benefits are obtained at doses of 120-160 mg/day [82], although it is possible to obtain certain benefits at a dosage of 80 mg/day, thereby ameliorating the adverse effects of treatment [78]. The benefit yielded by tacrine is particularly evident in cognitive function, functional ability and global scales of mental deterioration. The clinical relevance of benefit may be inferred by comparison with the usual evolution of cognitive function in AD. The MMSE falls by 3 points every 6-12 months [95] and the cognitive component of the ADAS rises by 7 points per year [96] in mild to moderate AD in the absence of treatment. It is therefore estimated that tacrine, at a dosage of 80-160 mg/day over a period of 6-30 weeks, slows the course of AD by approximately 6 months [71, 74-76, 78, 82]. This benefit is considered clinically relevant by the US Food and Drug Administration [97], even when it represents no more than 10% of the clinical phase of the disease [98, 99].

However, the adverse effects of tacrine--both cholinergic and hepatic--mean that only one-third of all patients receive the more effective dosage levels of 160 mg/day [82]. Furthermore, at least 50% of patients on therapeutic dosages suffer adverse effects [100] and only 20% of patients treated with high doses experience the benefits of the medication, with such benefits tending to disappear a few weeks after medication is halted [39, 41]. It is, therefore, unlikely that more than 20% of patients initially treated with tacrine will benefit from the treatment.

It is not known which AD patient subgroup could benefit from the treatment. Information on the long-term effects of tacrine (periods exceeding 7 months) and on its effects on quality of life, patient institutionalization and mortality and patient burden on caregivers, is inadequate. Tile cost-effectiveness of tacrine in AD is also unknown, although it would have to delay institutionalization by a minimum of 9 months for the treatment to be cost-effective [101].

In conclusion, tacrine shows a modest degree of efficacy among a small proportion of patients with mild to moderate AD and has adverse effects which limit its clinical usefulness. However tacrine should be used as a benchmark for the evaluation of other aminoacridines such as donepezil, galantamine and metrifonate as anti-dementia drugs. The ideal drug would have greater clinical efficacy than tacrine, a lower dosage frequency, greater safety and lower cost.

Acknowledgements

We thank Carlos Rodriguez Pascual and Teresa Olcoz Chiva for their helpful comments on an earlier draft of the paper and Michael D. Benedict for preparing the English-language version. This study was funded in part by grant no. 96/0477 from the Fondo de Investigacion Sanitaria (Health Research Fund).

Key points

* This systematic review of 49 clinical trials of tacrine in Alzheimer's disease showed that one-third of patients were withdrawn from treatment.

* Most withdrawals were because of cholinergic side effects or elevations in serum transaminase concentrations.

* Some patients with mild to moderate Alzheimer's disease show clinical benefit on tacrine but these patients cannot be identified before starting treatment.

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Received 5 August 1997

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