Baseline Medication Use in the Alzheimer’s Disease Neuroimaging

Initiative (ADNI).

Dr. Noam Epstein, MD, MSBoard Certified Neurologist

Board Eligible Clinical Pharmacologist

Outline

• Introduction– Current symptomatic Alzheimer’s disease (AD)

and mild cognitive impairment (MCI) treatments– Polypharmacy and Beer’s list– ADNI

• Objectives are to describe:– Polypharmacy – MCI and AD treatment in the ADNI cohort

• Results and Conclusions

Current AD Treatments

• Cholinesterase inhibitors– Donepezil (mild to severe) [11][16][17] – Galantamine (mild to moderate) [12]– Rivastigmine (mild to moderate) [13]

• NMDA partial antagonist– Memantine (moderate to severe) [16]

• The combination of donepezil and memantine in moderate to severe stage AD is more effective and has a lower rate of discontinuation than donepezil monotherapy [17].

Current MCI Treatments

• Many physicians recommend using cholinesterase inhibitors for symptomatic treatment of cognitive dysfunction in MCI, considering this entity the earliest stage of AD.

Current MCI Treatments

• A recent meta-analysis of placebo-controlled trials of the cholinesterase inhibitors in MCI showed that none of these medications delayed the onset of AD and that their adverse effects were frequent [18].

• The FDA has issued a health care provider alert for use of galatamine as a symptomatic therapy for MCI due to the greater number of deaths with galantamine treatment as compared with placebo in MCI in two recent double-blind placebo-controlled trials [19].

Polypharmacy in the Elderly

• Some have defined polypharmacy as subjects taking >5 daily medications [1-4]. Others have defined polypharmacy as >3 daily medications [5]. One study stratified polypharmacy categories by number; 2-3 medications (minor), 4-5 medications (moderate), and >5 medications (major) [6].

• Variously 36% to 61% of elderly individuals have been reported to take ≥4 medications daily [5, 7].

Polypharmacy and Adverse Effects

• The probability of an adverse drug effect or interaction increases from 13% for two medications to 82% for more than seven medications[8] and nears 100% when ten or more medications are taken [9].

• A previous study has suggested that while polypharmacy is a predictor of health outcomes, neither main diagnosis nor number of diagnoses on hospital admission are similarly good predictors of health outcomes [1].

Beer’s List

• The Beer’s list, generated by a US consensus panel of experts in pharmacology, represents a subset of medications which for various reasons such as; sedation, cardiovascular risk and mechanism of elimination, are potentially more dangerous in the elderly [10].

• All subjects in ADNI are elderly and the medications detailed on the Beer’s list may be inappropriate or dangerous for them.

ADNI Study Design (n=800)• ADNI is the largest MCI longitudinal cohort study using frequent

multimodal imaging over three years. – 200 AD subjects– 400 MCI subjects– 200 age matched controls

• Outcomes – Rate of volume change of whole brain and other regions of

interest– Neuropsychiatric testing– Plasma and CSF biomarkers– Rate of conversion from MCI to AD– Adverse events

Medication Use in ADNI

• A description of medication use at baseline in ADNI has not been reported in the literature.

• ANDI subjects were taking many medications, some of which may have had beneficial effects on cognition and others of which may have been deleterious.

• Therefore, the objectives of this study were to describe polypharmacy, and MCI and AD treatment patterns in the ADNI cohort.

Results

Polypharmacy Histogram in ADNI

Top 10 Beer’s Medications in ADNI

• Estrogen (29)• Celecoxib (22)• Doxazosin (21)• Naproxen (21)• Digitoxin (21)• Fluoxetine (15)• Nifedipine (8)• Oxybutynin (7)• Amiodarone (6)

• Benzodiazepines (18)– Alprazolam (7) – Temazepam (3)– Lorazepam (3) – Diazepam (2) – Chlordiazepoxide– Clorazepate – Oxazepam

Polypharmacy in ADNI

• 85% of ADNI patients were taking 4 or more medications daily.

• Mean number of medications per subject in ADNI is higher than previous reports [2, 5, 7] in the elderly.

• The number of subjects taking one or more medications from Beer’s list was also high 22%.

• Polypharmacy and number of Beer’s medications were not significantly different between the three diagnostic groups.

MCI and AD Treatment in ADNITreatment Number of

SubjectsMCI (n=400) AD (n=184)

Donepezil 189 120(30%) 69(37%)

Galantamine 30 16(4.0%) 14(7.6%)

Rivastigmine 11 7 (1.7%) 4(2.2%)

Memantine 21 8(0.1%) 13(7.1%)Donepezil and

Memantine 88 33(8.3%) 55(30%)Galantamine and

Memantine 13 2(0.5%) 11(6.0%)Rivastigmine and

Memantine 7 1(0.3%) 6(3.2%)

Cholinesterase Treatment by Diagnosis

A) MCI cohort B) AD cohort

Off Label MCI Treatment in ADNI

• Combination therapy is common in both AD and MCI subjects. • Memantine therapy in MCI is not supported by professional

society recommendations or evidence based clinical resources.

• The use of cholinesterase inhibitors in MCI is supported by profession society recommendations with equivocal data from clinical prospective trials. In the case of galantamine, the FDA has specifically recommended against its use in MCI.

• Despite the limited clinical evidence, there is biological plausibility for the idea that MCI precedes AD and AD therapies might be expected to have beneficial effect in MCI.

Gender and Education are Associated with Cholinesterase Inhibitor Treatment of AD

• There was a significant difference in cholinesterase inhibitor treatment by gender (p = 0.011). – Men 93.8% – Women 78.4%

• The OR for cholinesterase inhibitor treatment for male gender was 3.6 with 95% CI of 1.4 to 9.7.

• There was a significant positive association of cholinesterase inhibitor treatment with years of education (p = 0.036).

• The OR for cholinesterase inhibitor treatment for each additional year of education was 1.17 with 95% CI of 1.01 to 1.35.

Disease Severity is Associated with Memantine Treatment of AD

• There was no significant association of cholinesterase treatment with disease severity defined by– Rey Auditory Verbal Learning Test (AVLT)– Clinical Dementia Rating Sum of Boxes (CDR-SB)– Left entorhinal cortex thickness – Left hippocampal volume (LHV)

• There was a significant positive association of memantine treatment with disease severity defined by CDR-SB (p = 0.016).

• The OR for memantine treatment for disease severity defined by each additional point of CDR-SB was 1.27 with a 95% CI of 1.05 to 1.53.

Recruitment in the MCI Group

• In the MCI group there was a difference in recruitment by gender.

• In the normal elderly and AD groups 47.8% of subjects were female while in the MCI group 35.8% of subjects were female (corrected p <0.02).

• In the MCI group 257 men were recruited as compared to only 143 women.

Age and Disease Severity are Associated with Cholinesterase Inhibitor Treatment of MCI

• Significant independent variables negatively associated with cholinesterase treatment in MCI included age (p = 0.009) and disease severity define by AVLT (p = 0.014) and LHV (p = 0.023).

• Disease severity defined by CDR-SB (p = 0.003) was positively associated with cholinesterase treatment in MCI.

Gender, Education, Age and Disease Severity are Associated with Memantine Treatment of MCI

• There was a significant difference in treatment with memantine by gender (p = 0.025). – Men 13.6%– Women 6.3%

• There was a significant positive association of memantine therapy with years of education (p = 0.023).

• Significant independent variables negatively associated with memantine treatment in MCI included age (p = 0.008) and disease severity defined by AVLT (p < 0.001) and LHV (0.024).

Logistic Regression Models

MCI Cholinesterase TreatmentOR 95% CI P-value

Age 0.959 0.930 0.989 0.0085

AVLT 0.969 0.945 0.994 0.0141

CDR-SB 1.453 1.137 1.856 0.0028

LHV 0.604 0.391 0.933 0.0231

MCI Memantine TreatmentOR 95% CI P-value

Age 0.934 0.888 0.982 0.0079

Gender 2.577 1.106 6.001 0.0282

Education 1.157 1.020 1.312 0.0229

AVLT 0.913 0.868 0.960 0.0004

LHV 0.419 0.197 0.891 0.0239

Previous analysis of the ADNI data [20] has shown that loss of hippocampal volume is the most sensitive MRI measure of disease progression from MCI to AD over one year.

This data shows hippocampal volume is also negatively associated with baseline treatment in MCI.

AD Treatment Summary• Men were nearly four times more likely to be treated with a

cholinesterase inhibitor than women.• Subjects with more education were treated with a cholinesterase

inhibitor more frequently than subjects with less education. • Cholinesterase inhibitors were given with no difference in

treatment frequency by disease severity while memantine was preferentially given to subjects with more severe disease defined by CDR-SB.

• These findings were expected because the most commonly prescribed cholinesterase inhibitor donepezil is FDA approved for all stages of AD while memantine is FDA approved only for the moderate and severe stages of AD.

MCI Treatment Summary

• All treatment was less frequent among older subjects. • Men were nearly three times more likely to be treated with

memantine than women. • Subjects with more education were more likely to be treated

with memantine than subjects with less education. • All treatment was prescribed more frequently to patients

with more severe disease as expected. • This was reflected by the increase in treatment frequency

with higher CDR-SB or lower AVLT score and left hippocampal volume.

Possible Explanations for the Treatment Differences by Gender

• 1) Proxy treatment decisions [30, 31]– Male caretakers are less likely to select treatment– Spousal caregivers and women adult children or

other caregivers are more likely to select treatment

• 2) Male physicians• 3) Biological rational

– Lower weight – Other physiological factors?

Conclusions

• In the MCI group there was a significant recruitment difference by gender. This difference may be difficult to adjust for when analyzing the results of ADNI.

• In the MCI group, treatment was negatively associated with age.

• All treatment was positively associated with years of education.

• Finally, gender may play a role in the diagnosis of MCI and treatment of MCI and AD, both of which warrant further investigation.

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Acknowledgements

• Neurology– Dr. Martin Farlow, MD

• Radiology– Dr. Andy Saykin, PsyD – Shannon Risacher

• Biostatistics – Dr. Sujuan Gao, PhD