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Impact of Tacrine in the Care of Patients With Alzheimer's Disease What We Know One Year After FDA Approval Committee on Aging: Group for the Advancement ofPsychiatry Copyright @ 1994 American Association for Geriatric Psychiatry T his September marks the first anniversary of the FDA's approval of tacrine as a medication for the treatment of mild-to.. moderate Alzheimer's disease (AD); it is a useful time to consider the drug's impact on patient care. The findings on the efficacy of high-dose tacrine reported by Knapp et al. 1 were key in the FDA's review of the new drug application and demonstrated to scientists t clinicians, families, and patients that it was feasible to improve cognitive performance through pharmacological interven.. tions. However, the limited benefits observed. together with the high prevalence of adverse events-primarily hepatotoxicity and cllolinergic symptoms-resulted in a lAMA editoria1 2 accompanying the Knapp paper that stated: Ultimately, better drugs are needed to treat patients with Alzheimerts disease.... New drugs must be developed that reverse the pathology underlying Alzheimer's disease, rather than temporarily palliate the process. Until then, tacrine may be a reasonable drug to try for selected patients who, with their caregivers, agree that the problems and costs are worth the potential benefit (p. 1024). Although tacrine is the first drug approved specifically for the treatment of mild-ta-moderate AD, it offers only symptomatic treatment and not a revolutionary advance in patient care. It is not specific for brain acetylclloline- sterases, and it produces systemic cholinergic side effects as well as risks of llepatotoxicity-both of which may be serious and may limit the ability of patients to tolerate the drug in effective doses. Moreover, the drug is intended for use with those patients who may be the least reliable in reporting problems, patients who must rely heavily on the judgment and beneficence of profeSSionals. This led the lAMA editorial to continue: Essential components of a treatment plan are regular objective cognitive assessment with frequent review of the goals of thempy, weekly transaminase monitoring dUring the titration phase of therapy, and patient and caregiver counseling and education, with planning for the still-inev- itable decline of the cognition and function of the patient with Alzheimer's disease (p. 1024). The most basic conclusion to. be drawn from the .available research on tacrine, together with approximately 1 year's experience with its clinical use, is that this new drug can add to, but it cannot and should not replace current psychiatric and general medical approaches to the evaluation and care of patients with dementia. First, tllere is the differential diagnosis of the protean causes of confusion of elderly patients. Without a detailed THE AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY 285
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Page 1: Impact of Tacrine in the Care of Patients With Alzheimer's Disease: What We Know One Year After FDA Approval: Committee on Aging: Group for the Advancement of Psychiatry

Impact ofTacrine inthe Care ofPatients WithAlzheimer'sDiseaseWhat We KnowOne Year AfterFDA Approval

Committee on Aging:Groupfor theAdvancementofPsychiatry

Copyright @ 1994 AmericanAssociation for Geriatric Psychiatry

This September marks the first anniversary of the FDA'sapproval of tacrine as a medication for the treatment

of mild-to..moderate Alzheimer's disease (AD); it is a usefultime to consider the drug's impact on patient care. Thefindings on the efficacy of high-dose tacrine reported byKnapp et al. 1 were key in the FDA's review of the newdrug application and demonstrated to scientists t clinicians,families, and patients that it was feasible to improvecognitive performance through pharmacological interven..tions. However, the limited benefits observed. togetherwith the high prevalence of adverse events-primarilyhepatotoxicity and cllolinergic symptoms-resulted in alAMA editoria12 accompanying the Knapp paper thatstated:

Ultimately, better drugs are needed to treat patients withAlzheimerts disease....New drugs must be developed thatreverse the pathology underlying Alzheimer's disease,rather than temporarily palliate the process. Until then,tacrine may be a reasonable drug to try for selected patientswho, with their caregivers, agree that the problems andcosts are worth the potential benefit (p. 1024).

Although tacrine is the first drug approved specificallyfor the treatment of mild-ta-moderate AD, it offers onlysymptomatic treatment and not a revolutionary advance inpatient care. It is not specific for brain acetylclloline­sterases, and it produces systemic cholinergic side effectsas well as risks of llepatotoxicity-both of which may beserious and may limit the ability of patients to tolerate thedrug in effective doses. Moreover, the drug is intended foruse with those patients who may be the least reliable inreporting problems, patients who must rely heavily on thejudgment and beneficence of profeSSionals. This led thelAMA editorial to continue:

Essential components of a treatment plan are regularobjective cognitive assessment with frequent review of thegoals of thempy, weekly transaminase monitoring dUringthe titration phase of therapy, and patient and caregivercounseling and education, with planning for the still-inev­itable decline of the cognition and function of the patientwith Alzheimer's disease (p. 1024).

The most basic conclusion to. be drawn from the.available research on tacrine, together with approximately1 year's experience with its clinical use, is that this newdrug can add to, but it cannot and should not replacecurrent psychiatric and general medical approaches to theevaluation and care of patients with dementia.

First, tllere is the differential diagnosis of the proteancauses of confusion of elderly patients. Without a detailed

THE AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY 285

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GAP Position Statement

286

history and evaluation, conditions that may be confusedwith AD include drug-related cognitive impairment, de­pression, and a variety of specific medical conditions. Theuse of tacrine in conditions other than AD is not indicated;it creates unnecessary risks and costs for both patients andtheir families. Even in patients who do have AD, thedisease is frequently complicated by treatable componentsof cognitive impairment from drug side effects, psychiatricsyndromes, or general medical conditions. Thus, prescrip­tion of tacrine should be considered only after the diag­nosis of AD has been established and reversiblecomponents of cognitive impairment have been excludedthrough a comprehensive evaluation.

Second, it is important to recall that the randomizedclinical trials on tacrine were conducted in subjects whowere essentially free of the comorbid medical conditionsand concomitant drug therapies that are common amongelderly patients. The safety of tacrine in patients withsignificant cardiac, pulmonary, gastrointestinal, and uro­logical disease is currently not known, and the specialrisks in frail elderly patients-including patients with poororal intake that may be further compromised by thedrug-have not been evaluated. The lAMA editorial2

called attention to the specific pharmacokinetic drug inter­actions that may occur when tacrine is prescribed topatients taking cimetidine or theophylline, drugs that aremetabolized by the same cytochrome P450 enzyme. But thepossibility of more widespread, less specific drug interac­tions that may occur in patients experiencing hepatotox­icity has not been evaluated. Thus, the data that arecurrently available do not allow clinicians to estimate thepotential risks of tacrine in the majority of elderly patientswith AD.

Third, the availability of tacrine does not decrease theimportance of treating noncognitive symptoms, such asagitation, aggressiveness, depression, hallucinations, anddelusions, that may increase disability and caregiver bur­den. Thus, use of tacrine represents only one of thetreatment options that should be considered in an individ­ualized treatment plan.

Tacrine was approved after review of a study in whichsubjects were randomized to 30 weeks of treatment withplacebo or doses oftacrine up to 160 mglday.l To evaluatethe potential impact of tacrine in the care of patients withAD, it is useful to review the benefits observed. In this trial,data from 181 subjects randomized to placebo treatmentand 238 assigned to dose titration up to 160 mg/day wereavailable for a 3D-week intention-to-treat analysis. How­ever, only 116 placebo and 64 experimental subjects

VOLUME 2 • NUMBER 4 • FALL 1994

Page 3: Impact of Tacrine in the Care of Patients With Alzheimer's Disease: What We Know One Year After FDA Approval: Committee on Aging: Group for the Advancement of Psychiatry

assigned to receive 160 mg/day completed treatment. Themost robust drug/placebo differences were those for thetreatment completers. In these analyses, placebo patientsdeclined on the Alzheimer's Disease Assessment Scale­Cognitive Subscale (ADAS-Cog) by an average of 2.0points, whereas those receiving 160 mg/day of tacrineimproved on average by 2.1 points.

There were not, however, any significant differencesbetween groups in measures of self-care or functionalperformance. Among those who completed the trial, 40%of patients receiving 160 mg/day and 25% of those receiv­ing placebo improved by 4.0 points or more on theADAS-Cog-an amount comparable to the deterioration inAD patients that might be expected over a period of 6months. Thus, "significant" improvement in cognitive per­formance on the ADAS-Cog, specifically due to tacrine,occurred in approximately 15% C4QOAl of patients receivingthe drug who improved by 4.0 points minus 25% of thosereceiving placebo who improved by 4.0 points) of patientsable to tolerate high-dose treatment. However, the treat­ment completers represented only 270/0 of those initiallyrandomized to 160 mg/day and 64% of those assigned toplacebo.

In the intention-ta-treat analysis that included essen­tially all of the randomized patients, placebo patientsdeclined on the ADAS-Cog by an average of 2.5 points,and high-dose tacrine patients declined by 0.5 points.Looking again at the total number of patients initiallyentering the trial, 27°h of the patients assigned to treatmentwith 160 mg/day of tacrine improved by 4.0 points ormore on the ADAS-Cog, compared to 200/0 of those as­signed to placebo. Thus, in the more conselVative inten­tion-ta-treat analysis, only 70/0 (270/0 of patients assigned todrug who improved by 4.0 points, minus 20% of thoseassigned placebo who improved by 4.0 points) of subjectsderived a "significant" benefit from tacrine.

From a practical perspective, the finding that only aminority .of patients given tacrine will benefit from itdemands that when clinicians prescribe the drug, they­together with patients and/or families-should formulateplans that will determine what evidence for cognitive andfunctional gains will setve as grounds for continuingtreatment beyond the time required for a therapeutic trial.On more conceptual grounds, the fact that a drug exhib­iting tacrine's profile of benefits and risks was approvedby the FDA allows us to use the magnitude of its thera­peutic effects as a yardstick, of sorts, for measuring therelative values of established interventions targeting treat­able causes of disability in patients with dementia.3 The

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GAP Position Statement

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7-150/0 (depending on how conservative an analysis isused) of patients who benefit from treatment with tacrineis approximately equal to the 100/0 of those presenting forevaluation of cognitive deficits at tertiary care centers whoare found to have drug toxicity as a cause or componentof cognitive decline.4 It is less than the estimated 19% ofpatients with AD with significant depression) the 33% withdelusions, the 130/0 with hallucinations t and the evengreater number of patients who exhibit significant agita­tion, for whom treatment of these problems can reduceexcess disability,s.6

The most compelling evidence for the effectiveness of"classical" treatment for patients with AD was recentlyreported by Mittelman and co-workers)' who randomizedpatients together with their families to usual care or aprogram targeting treatment to spouse-caregivers; inter­ventions included individual and family counseling, edu"cation, attendance at a caregivers' support group, and amechanism for facilitating new arrangements for assis­tance whenever the patient's or the caregiver's physical ormental condition changed. Among their measures of out­come, they found that 23.30/0 of the patients from the"usual treatment" control groups required nursing homeplacement within 1 year, compared to only 10.7% of thosereceiving the experimental intervention. The psychosocialintervention apparently prevented the need for nursinghome placement in 12.60/0 of patients. In comparison t

tacrine led to improvement in a measure of cognitiveperformance, without any apparent impact on measuresof self-care, in 7-15%. Although we are admittedly "com­paring apples and oranges,tt it is impossible to escape theconclusion that the classical, established uapplesu are atleast as valuable as the new "oranges.u

One year after tacrine was approved, it is now appar­ent that this approval was a significant event in theevolution of care for patients with AD, but one with onlylimited tangible benefits. Although tacrine adds to thetreatment options available to patients, families, and phy­sicians, it brings incremental gains to an established arrayof options. In fact, approval of such a drug represents astrong source of validation for the importance of alreadyavailable clinical strategies for recognizing and treatingreversible causes or components of disability. Tacrine canadd to established opportunities for treatment of patientswith AD, but it should in no way replace them. Thisprinciple should be obvious to those in the field ofgeriatric psychiatry, but it may not be apparent to patients'families or to primary care practitioners. It is important thatthis message be brought to them.

VOLUME 2 • NUMBER 4 • FALL 1994

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The members of the GAP Committee on Aging:

Karen Blank, M.D.Josepha A. Cheong) M.D., FellowGene D. Cohen, M.D., Ph.D.Charles Gaitz, M.D.Gary Gottlieb) M.D.Ira R. Katz, M.D., Ph.D.Andrew Leuchter, M.D.Gabe Maletta, M.D., Ph.D.Richard Margolin, M.D.Kenneth Sakauye, M.D.Charles Shamoian, M.D., Ph.D.

References

1. Knapp M}, Koopman OS, Solomon PR, et al: A 30-week randomizedcontrolled trial of high-dose tacrine in patients with Alzheimer'sdisease. JAMA 1994; 27:985-991

2. Winkler MA: Tacrine for Alzheimers' disease: which patient, whatdose (editoria1)? ]AMA 1994; 271:1023-1024

3. Committee on Aging, Group for the Advancement of Psychiatry: ThePsychiatric Treatment of Alzheimer's Disease. New York. Brunner­Mazel, 1988

4. Larson EB. Kukall WA, Bucher D, et al: Adverse drug reactionsassociated with global cognitive impairment in elderly persons. AnnIntern Med 1987; 107:169-174

5. Wragg R, Jeste D: Overview of depression and psychosis andAlzheimer's disease. Am] Psychiatry 1989; 146:577-587

6. Teri L, Rabins P, Whitehouse I), et al: Management of behaviordisturbance in Alzheimer's disease: current knowledge and futuredirections. Alzheimer Dis Assoc Disord 1992; 6:77-88

7. Mittelman MS, Ferris SH, Steinberg G, et al: An intervention thatdelays institutionalization of Alzheimer's disease patients: treatmentof spouse caregivers. Gerontologist 1993; 33:730-740

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