Pharmacotherapy Update: Newer Data on Older Medications

The advancements in pharmacotherapeutic knowledge continue to grow at an alarming rate. It is nearly impossible to keep up with the primary literature, even in fields of medicine that are narrowly focused. This review of recently published literature of relevance to the care of older adults is based in part on a presentation from the 2007 AGS meeting in Seattle, “Pharmacotherapy Update 2007.” A brief summary of several studies is provided below. Brief information regarding the study methods, findings, and conclusions will be discussed. However, it is important for clinicians to decide independently how these studies may apply to individual patients. Clinicians are encouraged to refer to the original articles to find details of the study methodology, study subject characteristics, and to help determine the applicability to patient care.

Neurology/Central Nervous System

Antipsychotics in Alzheimer’s Disease
This study is known as the CATIE-AD (Clinical Antipsychotic Trials of Intervention Effectiveness – Alzheimer’s Disease) study and is a part of the larger group of CATIE studies supported by the National Institute of Mental Health. The study included 421 patients with behavioral symptoms of Alzheimer’s disease (AD) with a mean age of 78 years and a mean Mini-Mental State Examination (MMSE) score of approximately 15. Study subjects were randomized to treatment with either olanzapine, quetiapine, risperidone, or placebo for up to 36 weeks. The main outcomes of the study were time to discontinuation for any reason (efficacy, safety, tolerability) and the number of subjects with at least minimal improvement as assessed by the Clinical Global Impression of Change (CGIC) scale at week 12. The mean doses used in the study were olanzepine 5.5 mg per day, quetiapine 56.5 mg per day, and risperidone 1 mg per day. For the primary outcomes, there were no significant differences in time to discontinuation between any of the treatment groups and no significant differences among the groups in improvement with the GGIC scale. The median time to discontinuation ranged from 5.3 weeks with quetiapine to 8.1 weeks with olanzapine. Improvement based on the CGIC scale ranged from 21% with placebo to 32% with olanzepine. Time to discontinuation due to a lack of efficacy favored risperidone (26.7 weeks) and olanzapine (22.1 weeks) over the other groups, while discontinuation due to adverse effects favored placebo at 5% (16% with quetiapine, 18% with risperidone, and 24% with olanzapine). In general, the adverse effects of antipsychotic treatments in persons with AD seems to negate the potential benefits. In addition, other concerns regarding the safety of antipsychotic medications in persons with AD need to be considered.

Reference
1. Schneider LS, Tariot PN, Dagerman KS, et al; CATIE-AD Study Group. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med2006;355:1525-1538.

Donepezil in Severe Alzheimer’s Disease
When the cholinesterase inhibitors were first introduced, these medications were indicated for use in patients with mild-to-moderate AD. The majority of studies with cholinesterase inhibitors have been conducted in patients with MMSE scores of 10 or greater. This study, performed in Sweden, specifically evaluated donepezil in the treatment of severe AD and included 248 nursing home patients with a mean MMSE score of 6. The trial was a double-blind, placebo-controlled, parallel-group design and was 6 months in duration. Patients assigned to donepezil started at 5 mg per day, and increased to 10 mg per day after 30 days. The primary outcomes of the study were change from baseline to 6 months in the Severe Impairment Battery (SIB) and the Alzheimer’s Disease Cooperative Study activities of daily living inventory for severe Alzheimer’s Disease (ADCS-AD severe). The SIB is an assessment of cognitive dysfunction, and the ADCS-AD assesses functional abilities with basic and complex activities. Patients treated with donepezil had statistically significant improvement in SIB scores (5.7; 95% confidence interval [CI], 1.5-9.8; P = 0.008) and declined less in the ADCS-AD severe scores (1.7; 95% CI, 0.2-3.2; P = 0.03) at 6 months. More patients in the donepezil-treated group discontinued treatment due to side effects, 16% versus 7%. Of the most common adverse effects, diarrhea and hallucinations were reported at more than twice the rate with donepezil as compared to placebo (9% versus 3% and 6% versus 1%, respectively). Donepezil is now FDA-approved to treat mild, moderate, and severe AD as of October 2006.

Reference
1. Winblad B, Kilander L, Eriksson S, et al; Severe Alzheimer’s Disease Study Group. Donepezil in patients with severe Alzheimer’s disease: Double-blind, parallel-group, placebo-controlled study [published corrections appear in Lancet 2006;367(9527):1980 and Lancet 2006;368(9548):1650]. Lancet 2006;367(9516):1057-1065.

Homocysteine and Cognition
Elevated concentrations of homocysteine have been associated with worse cognitive function in older adults. As such, there has been an interest in determining whether lowering homocysteine improves cognitive performance. This two-year study enrolled 276 healthy subjects (patients with dementia were excluded) age 65 years or older to randomized, double-blind, placebo-controlled treatment with a daily supplement containing folate (1000 mcg), B₆ (10 mg), and B₁₂ (500 mcg) or matching placebo. Baseline homocysteine concentrations had to be at least 13 μmol/L or higher. A battery of cognitive tests served as the primary endpoints and were performed at baseline, at year 1, and at year 2. Although plasma homocysteine concentrations were an average of 4.36 μmol/L lower in the supplement group at year 2, there was no significant difference between the supplement group and the placebo group in the overall cognitive testing scores. In one test, the supplement group actually performed worse than the placebo group at year 2. It remains to be shown whether vitamin supplementation and lowering of homocysteine may be useful in different populations than the healthy population without dementia studied here. Also, a longer duration of treatment may be necessary to achieve beneficial results on cognition. Costs of supplements and how additional therapies may contribute to medication burden and risk of polypharmacy are important considerations as well.

Reference
1. McMahon JA, Green TJ, Skeaff CM, et al. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med 2006;354:2764-2772.

Antioxidants
Oxidative damage has been implicated in many human diseases. As a result, antioxidant supplements have been studied frequently to determine whether treatment may prevent disease and alter disease progession. This meta-analysis sought to assess mortality in studies that have used various antioxidant interventions. Studies included interventions involving beta carotene, vitamin A, vitamin C, vitamin E, and selenium, either alone or in combination, versus placebo or no treatment. A total of 68 studies involving more than 200,000 participants were included in the analysis. In the combined analysis including all studies and all antioxidant supplements together, no significant effect on mortality was observed (RR, 1.02; 95% CI, 0.98-1.06). Analyses of the 47 higher-quality studies (180,000 participants), combining all antioxidant interventions, showed significantly increased mortality (RR, 1.05; 95% CI, 1.02-1.08). Additional analyses of the higher-quality studies showed that the use of beta carotene (RR, 1.07; 95% CI, 1.02-1.11), vitamin A (RR, 1.16; 95% CI, 1.10-1.24), and vitamin E (RR, 1.04; 95% CI, 1.01-1.07) were all associated with increased mortality; however, vitamin C and selenium were not. The inclusion of many studies with varying interventions, and in diverse patient populations, makes it difficult to interpret how to apply these results. In particular with vitamin E, which has been studied with positive results in Alzheimer’s disease (NEJM 1997), this may provide additional evidence to suggest that this intervention may carry some risks.

References
1. Bjelakovic G, Nikolova D, Gluud LL, et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: Systematic review and meta-analysis [published correction appears in JAMA 2008;299(7):765-766]. JAMA 2007;297:842-857.

2. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N Engl J Med 1997;336:1216-1222.

3. Miller ER 3rd, Pastor-Barriuso R, Dalai D, et al. Meta-analysis: High dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46. Published Online: November 10, 2004.

4. Petersen RC, Thomas RG, Grundman M, et al; Alzheimer’s Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairments. N Engl J Med 2005;352:2379-2388. Published Online: April 13, 2005.

5. Hayden KM, Welsh-Bohmer KA, Wengreen HJ, et al; Cache County Investigators. Risk of morality with vitamin E supplements: The Cache County Study. Am J Med 2007;120:180-184.

Medication versus Behavioral Therapy for Sleep
Insomnia is a common problem among older adults that is most commonly treated with pharmacologic measures. Unfortunately, many medications used to treat insomnia can have adverse effects, such as prolonged sedation, orthostasis, and cognitive impairment, as well as issues with dependency. Nonpharmacologic interventions, such as cognitive behavioral therapy (CBT), may be useful for improving sleep quality; however, there is limited evidence to compare pharmacologic interventions to CBT, particularly in older adults. This study evaluated both short-term and long-term clinical efficacy of CBT versus zopiclone in older adults with chronic primary insomnia. The study included 46 patients with a mean age of 61 years, with 22 women and 24 men. The CBT intervention included sleep hygiene, sleep restriction, stimulus control, cognitive therapy, and relaxation techniques. Patients were randomized to a 6-week treatment with either CBT (n = 18), zopiclone 7.5 mg each night (n = 16), or placebo medication (n = 12), with long-term follow-up at 6 months. Polysomnography and sleep diaries were used for outcome measures (total wake time, total sleep time, sleep efficiency, and slow-wave sleep) at baseline, 6 weeks, and 6 months. CBT improved total sleep time, sleep efficiency, and slow-wave sleep as compared to zopiclone at both 6 weeks and 6 months. Outcome measures with zopiclone were not substantially different from placebo. At 6 months, sleep efficiency was improved from 81% to 90% with CBT but was decreased slightly with zopiclone. CBT appears to be an effective sleep intervention in older adults, but the intervention used in this study may not be practical to implement (6 x 50-min sessions).

Reference
1. Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zoplicone for treatment of chronic primary insomnia in older adults: A randomized controlled trial. JAMA 2006;295:2851-2858.

Cardiovascular Disease

Stroke
A previous study, the Second European Stroke Prevention Study (ESPS-2), showed that the combination of aspirin plus extended-release dipyridamole was superior to aspirin alone in reducing vascular events, including stroke, in patients with a prior transient ischemic attack (TIA) or stroke. Earlier smaller studies evaluating aspirin and immediate-release dipyridamole did not show benefits of the combination as compared to aspirin alone. The European/Australian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) was developed to try and resolve the controversy surrounding the use of aspirin and extended-release dipyridamole in combination. More than 2700 patients with TIA or minor stroke within the previous 6 months were randomized to aspirin (30-325 mg QD) with or without extended-release dipyridamole 200 mg twice daily. The primary endpoint was the composite of vascular death, nonfatal myocardial infarction (MI) or stroke, or major bleeding, and patients were followed for an average of 3.5 years. Primary events occurred in 16% of subjects taking aspirin alone, as compared to 13% of patients taking the combination, (hazard ratio = 0.80; 95% CI, 0.66 – 0.98); (absolute risk reduction, 1.0 per year; 95% CI, 0.1 – 1.8). That means that 100 patients would need to be treated (NNT) for 1 year with the combination product to prevent one additional primary event. Patients taking the combination discontinued trial medication more frequently than those taking aspirin alone, primarily due to the side effect of headache.

A combination product is available containing extended-release dipyridamole 200 mg and aspirin 50 mg in a single capsule, although it is significantly more expensive than aspirin given alone. Whether the same results can be obtained by using generic immediate-release dipyridamole along with an aspirin is not clear. The differences in the pharmacokinetics of the extended-release dipyridamole compared to immediate-release dipyridamole may partly explain the differences in the findings between the more recent trials (ESPS-2, ESPRIT) and negative earlier trials using immediate-release dipyridamole.

Reference
1. ESPRIT Study Group; Halkes PH, van Gijn J, Kappelle LJ, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischemia of arterial origin (ESPRIT): Randomised controlled trial [published correction appears in Lancet 2007;369(9558):274]. Lancet 2006;367:1665-1673.

The author reports no relevant financial relationships.