Pharmacotherapy Update 2009, Part I: Cardiology, Neurology, and Psychiatry

This article is part I of a two-part series update on pharmacotherapy, and it focuses on cardiology, neurology, and psychiatry. Part II, which will be published in a subsequent issue of the Journal, will focus on infectious disease, positive Beers criteria, and pharmacist interventions.

Introduction

This article is intended to provide a review of recently published literature of relevance to the care of older adults. It focuses on studies that involve pharmacotherapeutic interventions, including both risks and benefits. It is important for clinicians to decide independently how the results of these investigations should be applied to individual patients; clinicians are encouraged to refer to the original articles to assist with making decisions and applying the results to patient care.

Cardiology

Aspirin/Dipyridamole versus Clopidogrel for Recurrent Stroke
Stroke is the leading cause of disability in adults, and approximately 1 in 5 nursing home residents have had a stroke. Aspirin reduces the risk of recurrent ischemic stroke by slightly more than 20% relative to placebo. The European Stroke Prevention Study 2 (ESPS-2)¹ and the European/Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT)² demonstrated a significant 21% relative risk reduction in recurrent ischemic stroke with the use of aspirin and extended-release dipyridamole as compared to aspirin alone. Studies with clopidogrel indicate a small relative risk reduction in recurrent stroke as compared to aspirin, particularly when including only patients with stroke as the qualifying event from the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial.³ Indirect comparisons suggest that the combination of aspirin/dipyridamole is better than clopidogrel for secondary stroke prevention.⁴ The Prevention Regimen For Effectively Avoiding Second Strokes (PRoFESS) study⁵ was the first to directly compare aspirin plus extended-release dipyridamole to clopidogrel for secondary (noncardioembolic) stroke prevention. The study was originally designed to look at the combination of aspirin/dipyridamole versus the combination of clopidogrel/aspirin, but with the findings of excess bleeding with this combination in the Management of ATherothrombosis with Clopidogrel in High-risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke (MATCH) study,⁶ the clopidogrel/aspirin arm was changed to clopidogrel alone. The study enrolled more than 20,000 patients age 50 years and older (mean age, 66 yr) with ischemic stroke within 120 days. Patients were randomized to treatment with either aspirin 25 mg plus extended-release dipyridamole 200 mg twice daily or clopidogrel 75 mg once daily. The primary outcome of the study was recurrent stroke of any kind.

After a mean follow-up of 2.5 years, recurrent stroke of any kind occurred in 9.0% of the patients receiving aspirin/dipyridamole and 8.8% receiving clopidogrel (hazard ratio [HR] = 1.01; 95% confidence interval [CI], 0.92-1.11). The combined outcome of stroke, myocardial infarction (MI), or vascular death (secondary outcome) occurred in 13.1% of patients in each group. Major hemorrhagic events occurred more frequently in the aspirin/dipyridamole group, 4.1% as compared to 3.6% with clopidogrel (HR = 1.15; 95% CI, 1.00-1.32). Intracranial hemorrhage also occurred more frequently in the aspirin/dipyridamole group as compared to the clopidogrel group (1.4% vs 1.0%; HR = 1.42; 95% CI, 1.11-1.83). The combined risk of recurrent stroke or major hemorrhagic event was similar between the two treatments, 11.7% with aspirin/dipyridamole and 11.4% with clopidogrel (HR = 1.03; 95% CI, 0.95-1.11).

The PRoFESS study was designed to initially test for noninferiority of combined aspirin/dipyridamole as compared with clopidogrel. If this condition was satisfied, then the superiority of aspirin/dipyridamole as compared with clopidogrel could be tested. However, the initial testing for noninferiority was not met, using the margin developed by the study investigators—meaning we cannot rule out the possibility that aspirin plus extended-release dipyridamole is inferior to clopidogrel. Rather than answering the question that many had hoped would be answered with the PRoFESS study (“Is aspirin/dipyridamole superior to clopidogrel?”), we are now unsure whether aspirin/dipyridamole is as effective as clopidogrel, and maybe more important, whether either of these treatments is better than aspirin alone.

References

1. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996;143:1-13.

2. The ESPRIT Study Group, Halkes PH, van Gijn J, Kappelle LJ, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): Randomised controlled trial [published correction appears in Lancet 2007;369(9558):274]. Lancet 2006;367(9523):1665-1673.

3. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

4. Thijs V, Lemmens R, Fieuws S. Network meta-analysis: Simultaneous meta-analysis of common antiplatelet regimens after transient ischaemic attack or stroke. Eur Heart J 2008;29:1086-1092. Published Online: March 17, 2008.

5. Sacco RL, Diener HC, Yusuf S, et al; PRoFESS Study Group. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238-1251. Published Online: August 27, 2008.

6. Diener HC, Bogousslavsky J, Brass LM, et al; MATCH Investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): Randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331-337.

Clopidogrel and Aspirin in Patients with Atrial Fibrillation
Atrial fibrillation is the most common type of cardiac arrhythmia found in nursing home residents, and it increases the risk of stroke by a factor of five. Adjusted-dose warfarin decreases the risk of stroke associated with atrial fibrillation by nearly 70%, but also substantially increases the risk of major bleeding. Patients who are considered to be at low risk of stroke or who are not considered reasonable candidates for warfarin therapy are most often given aspirin, which reduces the risk of stroke by about 22%. The AF Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) studies were designed to evaluate the role of clopidogrel plus aspirin for prevention of stroke and other vascular events in patients with atrial fibrillation. The ACTIVE W study,⁷ reported in 2006, compared clopidogrel 75 mg/day plus aspirin 75-100 mg/day to warfarin (INR 2-3). The study was stopped early because of clear evidence for the benefit of warfarin over clopidogrel plus aspirin. The recently published ACTIVE A study⁸ was designed to evaluate aspirin 75-100 mg/day plus the addition of either clopidogrel 75 mg/day or placebo for stroke prevention in patients with atrial fibrillation who were not considered candidates for warfarin therapy.

To be enrolled in ACTIVE A, patients had to have atrial fibrillation at enrollment or at least two episodes of intermittent atrial fibrillation in the previous 6 months, and at least one additional risk factor for stroke: over age 75 years; hypertension; prior stroke, transient ischemic attack (TIA) or systemic embolism; heart failure; peripheral vascular disease; or age between 55 and 74 years with diabetes or coronary artery disease. More than 7500 patients were randomized and followed for approximately 3.5 years. More than two-thirds of the patients enrolled had CHADS2 scores of 1 or 2, and 13% had a prior history of stroke or TIA.⁹ The primary outcome of the study was the composite of stroke, MI, noncentral nervous system systemic embolism, or vascular death. The primary outcome occurred in 6.8% per year in patients receiving aspirin plus clopidogrel and 7.6% per year in those receiving aspirin plus placebo (relative risk [RR], 0.89; 95% CI, 0.81-0.98). This translates to a number needed to treat (NNT) of 125, meaning that 125 patients would need to be treated with aspirin plus clopidogrel for 1 year to prevent one additional vascular event. The difference in event rates was primarily due to a decrease in the risk of stroke in the aspirin plus clopidogrel group (2.4% per year vs 3.3% per year with aspirin plus placebo). Major bleeding occurred in 2.0% per year of patients with aspirin plus clopidogrel as compared to 1.3% with aspirin plus placebo (RR, 1.57; 95% CI, 1.29-1.92). For every additional 143 patients treated with aspirin plus clopidogrel for 1 year, one additional major bleeding event would be expected. The rates of intracranial bleeding (0.4% vs 0.2% per year) and fatal bleeding (0.3% vs 0.2% per year) were higher with aspirin plus clopidogrel. When combining the primary outcome and major bleeding episodes, there was no significant difference between the two treatment groups with regard to event rates (RR, 0.97; 95% CI, 0.89-1.06).

The mean age of the participants in this study was approximately 71 years, and, although patients residing in nursing homes were not specifically excluded from the trial, it is not clear whether any patients from nursing home settings were included. For the majority of patients included in ACTIVE A, the reason for not considering anticoagulation with warfarin was due to the physician’s judgment that warfarin was inappropriate (history of falls or head trauma, previous serious bleeding on warfarin, prior peptic ulcer disease, history of alcohol abuse, or long-term therapy with non-steroidal anti-inflammatory drugs). For patients who are not considered candidates for anticoagulation with warfarin, the use of aspirin plus clopidogrel (compared to aspirin alone) may slightly decrease the risk of vascular events, particularly stroke; however, this reduced risk is largely negated by the increased risk of major bleeding complications.

References

7. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): A randomised controlled trial. Lancet 2006;367:1903-1912.

8. ACTIVE Investigators, Connolly SJ, Pogue J, Hart RG, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009;360:2066-2078. Published Online: March 31, 2009.

9. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: Results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864-2870.

Neurology

Syncope and Cholinesterase Inhibitors
The cholinesterase inhibitors (ChoIs) are the most commonly prescribed medications used to treat the symptoms of Alzheimer’s disease and related dementias. Gastrointestinal side effects such as nausea, vomiting, and diarrhea are most frequently reported as related to the use of ChoIs. Although not well recognized, these medications can also potentiate vagal effects on the heart and produce bradycardia and increase the risk for syncope. Clinical studies of ChoIs have demonstrated low rates of syncope, but most studies have excluded patients with significant heart disease or those taking other medications that could slow heart rate.

A recent study investigated the relationship between the use of ChoIs and syncope-related outcomes in community-dwelling older adults with dementia.¹⁰ This investigation was a retrospective cohort study using healthcare databases from Ontario, Canada, and included over 80,000 community-dwelling older adults with a diagnosis of dementia. Patients residing in long-term care facilities at cohort entry were excluded from this study. There were two cohorts defined in the study: one included new users of ChoIs (19,803 patients), and the other included those who had not received ChoIs in the year prior to cohort entry (61,499 patients). Event rates (events per 1000 person-years) for hospital visits due to (1) syncope, (2) bradycardia, (3) permanent pacemaker insertion, and (4) hip fracture were calculated for the two cohorts. Analyses were risk-adjusted to account for differences in baseline characteristics, and separate analyses matching subjects for comorbid illness and propensity scores were done. Hospital visits for syncope occurred more frequently in treated subjects than in control subjects (31.5 vs 18.6 events per 1000 person-years; adjusted HR = 1.76; 95% CI, 1.57-1.98). Hospital visits for bradycardia (event rate, 6.9 vs 4.4; HR = 1.69; 95% CI, 1.32-2.15), permanent pacemaker insertion (4.7 vs 3.3; HR = 1.49; 95% CI, 1.12-2.00), and hip fracture (22.4 vs 19.8; HR = 1.18; 95% CI, 1.04-1.34) were also more common among users of ChoIs as compared to control subjects. For the outcome of hospital visits for syncope, the observed event rate would translate to a number needed to harm (NNH) of 78, or one additional syncope-related hospitalization for each 78 patients treated for 1 year. The NNH for bradycardia, pacemaker insertion, or hip fracture would be 400, 715, and 385, respectively.

Bradycardia and syncope are possible side effects of ChoIs, and these effects may not be widely appreciated. Although not specifically addressed in this study, patients who are on concurrent beta blockers, non-dihydropyridine calcium-channel blockers, digoxin, or other medications that also slow heart rate may be at greater risk for these symptoms. These risks should be considered when making decisions about treatment in patients with dementia. Memantine, the only other medication approved to treat dementia, has not been associated with bradycardia or syncope and would not be expected to based on mechanism of action.

Reference

10. Gill SS, Anderson GM, Fischer HD, et al. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: A population-based cohort study. Arch Intern Med 2009;169:867-873.

Psychiatry

Atypical Antipsychotics and Sudden Cardiac Death
Conventional antipsychotics have been associated with a dose-related increase in risk of sudden cardiac death via blockade of repolarizing potassium currents and prolongation of the QT interval. There are fewer cardiac safety data available for atypical antipsychotics. Despite evidence of electrophysiological effects similar to that of the conventional agents, the risk of sudden cardiac death relative to conventional antipsychotics is not well defined.

A recent study by Ray et al¹¹ was designed to compare the risk of sudden cardiac death between atypical and conventional antipsychotics using computerized Tennessee Medicaid data from January 1, 1999 to December 31, 2005. The study included individuals age 30-74 years who demonstrated regular use of medical care, were enrolled in Medicaid for at least 730 days, and had at least 1 qualifying day of antipsychotic use. Individuals were matched by age, gender, and first day of follow-up with two controls. Follow-up excluded hospitalization time and 30 days after discharge, as well as medications dispensed while in the hospital. A secondary analysis was preformed to create a control group propensity-matched for psychiatric illness and to control for confounding factors. Users of antipsychotic drugs with schizophrenia and related psychosis were excluded from this analysis. The resultant cohort consisted primarily of individuals with mood disorders treated with alternative medications. This cohort included analyses adjusted according to use or nonuse of antipsychotic medication and dosage of antipsychotic medication. Sudden cardiac death in the community was the primary end point.

There were 17.9 sudden cardiac deaths per 10,000 person-years of follow up. The unadjusted rate increased more than tenfold, from 4.7 deaths per 10,000 person-years for individuals age 30-34 years, to 47.6 deaths per 10,000 person-years for individuals age 70-74 years. Current users of antipsychotics had adjusted rates of sudden cardiac death about twice that of nonusers, with a positive dose-dependent relationship for each class. This rate was twice as high for men as it was for women. Current users of thioridazine in doses of 300 mg or higher had the greatest increased risk. Former users of antipsychotics did not have significantly increased risk of sudden cardiac death as compared to nonusers. The authors concluded that current users of atypical antipsychotics had a dose-dependent increase in the risk of sudden cardiac death, which is similar to that of individuals prescribed conventional agents.

Reference

11. Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009;360:225-235.

Antipsychotic Therapy and Short-Term Serious Events in Older Adults with Dementia
Antipsychotic medications are commonly used to treat behavioral and psychological symptoms of dementia and delirium in the geriatric population, although not indicated for this use. Upon nursing home admission, antipsychotics are initiated in 17% of patients within 100 days. Associated adverse drug reactions in this population include extrapyramidal symptoms, falls, hip fractures, cerebrovascular events, and death. The investigators used this study to determine the risk of developing any serious adverse event with short-term antipsychotic use in older adults with dementia.

This was a population-based retrospective study of all residents in Ontario, Canada, age 66 years and older, with a diagnosis of dementia who were prescribed antipsychotic medication between April 1, 1997 and March 31, 2004.¹² The population was divided into community-dwelling persons or nursing home residents who were propensity-matched to create three antipsychotic exposure groups: (1) none; (2) atypical antipsychotic use; or (3) first-generation antipsychotic use. The primary outcome was the composite of any adverse event identified within 30 days of study entry. A serious event was defined as one that results in death, is life-threatening, requires inpatient admission or lengthens hospital stay, or results in persistent or significant disability. 

The most frequently prescribed atypical antipsychotic was risperidone, followed by olanzapine and quetiapine. Haloperidol was the most frequently prescribed conventional antipsychotic, followed by loxapine and thioridazine. In the community cohort (n=6894 propensity-matched individuals with atypical antipsychotic exposure), 960 individuals (13.9%) experienced a serious event (140 hospital admissions for known serious events: 20 for extrapyramidal symptoms [EPS], 82 for fall/hip fracture, 47 for cerebrovascular event. There were 760 hospital admissions for other events). Of this group, 2.7% (186) individuals died. Those prescribed conventional or atypical agents were, respectively, 3.8 and 3.2 times more likely to experience any adverse event at 30 days follow-up versus matched controls.

In the nursing home cohort (n=6853 propensity-matched individuals with atypical antipsychotic exposure), 645 individuals (9.4%) experienced a serious event within 30 days of receiving a prescription for an atypical antipsychotic (80 hospital admissions for known serious events: 6 for EPS, 67 for fall/hip fracture, 11 for cerebrovascular event. There were 311 hospital admissions for other events). Of this group, 5.2% (355) individuals died. Those prescribed conventional or atypical agents were respectively 2.4 and 1.9 times more likely to experience any adverse event at 30 days follow-up versus matched controls.

The frequencies of adverse events was similar between the conventional and atypical antipsychotic groups in both cohorts. Use of a conventional or atypical antipsychotic significantly increased the risk of an adverse event versus matched controls. Authors concluded that this study is consistent with literature reporting findings that risk of death associated with antipsychotic therapy is increased, even with short-term use. Before initiating antipsychotic therapy, precipitating factors including pain management, medication withdrawal or side effects, undiagnosed medical or neurological illness, and environmental factors should be addressed.

Reference

12. Rochon PA, Normand SL, Gomes T, et al. Antipsychotic therapy and short-term serious events in older adults with dementia. Arch Intern Med 2008;168:1090-1096.

Single versus Dual-Action Antidepressants in Elderly Persons
The prevalence of major depressive disorder in the elderly is estimated to be 15-25% in nursing home residents, 15% in community-dwelling residents, and 25% for those with chronic medical illness. It is estimated that 60% of clinically significant cases remain untreated. Because of tolerability, selective serotonin reuptake inhibitors (SSRIs) have replaced dual-acting tricyclic antidepressants (TCAs) as first-line therapy for depression. Dual-acting serotonin-norepinephrine reuptake inhibitors (SNRIs) have provided an alternative to SSRIs as first-line therapy for depression and are preferred agents for those who do not respond to SSRIs. Both TCAs and SNRIs have a broader neuroreceptor spectrum versus SSRIs; however, superior clinical efficacy has not been determined.

Mukai and Tampi¹³ conducted a systematic review of antidepressant publications that included individuals age 59 years or older with a diagnosis of major depressive disorder. Differences in dose, duration of therapy, and sample population were evident between trials in this review. Both single- and dual-acting antidepressants were shown to be effective in the treatment of depression in the elderly, with no significant differences between the classes. However, there were significant differences noted in tolerability profiles of the agents in the elderly population.

The following information is specific to the data collected for this review. The most common adverse effects reported with SSRI treatment are listed as follows: escitalopram—headache, nausea, diarrhea, dry mouth, and dizziness; citalopram—dry mouth, headache, constipation, and dyspepsia; paroxetine—somnolence, dry mouth, headache, abnormal ejaculation, diarrhea, asthenia, nausea, constipation, dyspepsia, and decreased appetite; sertraline—nausea, dizziness, headache, diarrhea, dry mouth, insomnia, and somnolence; fluoxetine—psychiatric symptoms, gastric symptoms, tachycardia, dizziness, and abnormal taste.

For TCAs, the most common adverse effects are related to the anticholinergic properties of these medications. Adverse effects reported are listed as follows: amitriptyline—dry mouth and constipation; nortriptyline—dry mouth, constipation, sweating, impaired visual accommodation, impaired urination, tremor, orthostatic vertigo, headache, nausea, and insomnia; trimipramine—gastric symptoms, cardiac arrhythmia, elevated serum glutamate pyruvate transaminase, and abnormal vision.

The most common adverse effects for the SNRIs are listed as follows: venlafaxine—agitation, tremor, dry mouth, nausea, headache, constipation, anxiety, dizziness, stomachache, vertigo, tiredness, restlessness, psychiatric symptoms, and sweating; duloxetine—dry mouth, nausea, and diarrhea.

There continues to be a deficit in randomized controlled studies comparing efficacy and tolerability of different classes of antidepressants in the elderly population. This review did not confer a clinical advantage to use of a single- versus dual-acting antidepressant. When selecting an antidepressant, clinicians should consider their patients’ ability to tolerate the agent.

Reference

13. Mukai Y, Tampi RR. Treatment of depression in the elderly: A review of recent literature on the efficacy of single- versus dual-action antidepressants. Clin Ther 2009;31:945-961.

Dr. Bergman has been on the speaker’s bureau for Pfizer and Ortho-McNeil. The other authors report no relevant financial relationships.

Dr. Bergman is Assistant Professor, Dr. Ronald and Dr. Gonzalez are Clinical Assistant Professors, and Dr. Ruscin is Professor, Department of Pharmacy Practice, Southern Illinois University Edwardsville School of Pharmacy; and Drs. Bergman, Ronald, Gonzalez, and Ruscin are Adjunct Clinical Assistant Professors, Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield.