A Randomized, Double-Blind, Placebo-Controlled Tolerability Study of Intramuscular Aripiprazole in Acutely Agitated Patients With Alzheimer's, Vascular, or Mixed Dementia
Article Outline
Objectives
To evaluate the tolerability of intramuscular (IM) aripiprazole in patients with agitation associated with dementia.
Design
A 24-hour, double-blind, placebo-controlled, randomized study.
Setting
Sixteen healthcare facilities in the United States.
Participants
A total of 129 patients with acute agitation associated with Alzheimer's, vascular or mixed dementia in healthcare facilities.
Intervention
Patients were randomized to IM aripiprazole (5 mg, 10 mg, or 15 mg) or IM placebo administered in divided doses 2 hours apart.
Measurements
Safety assessments included adverse event (AE) reporting, vital signs, and electrocardiograms. Preliminary efficacy analyses used the Positive and Negative Syndrome Scale–Excited Component (PEC) scores and Agitation-Calmness Evaluation Scale (ACES).
Results
There was greater incidence of AEs with IM aripiprazole (50% to 60%) than IM placebo (32.0%), but over 90% were mild or moderate in severity. The incidence of oversedation was low. PEC scores showed greater improvements in agitation with IM aripiprazole 10 mg and 15 mg compared with IM placebo.
Conclusion
A total of 10 mg or 15 mg of IM aripiprazole administered in divided doses was safe and well tolerated for treatment of agitation associated with Alzheimer's, vascular, or mixed dementia in long-term care. Preliminary analysis showed greater efficacy compared with IM placebo.
Keywords: Acute agitation, intramuscular antipsychotic therapy, aripiprazole, dementia, tolerability
More than half of the long-term population residing in health care facilities has dementia. At some time, most of these patients manifest agitation that can result in verbal and physical aggression. Acute agitation can affect multiple systems, for example, the respiratory, cardiovascular, and musculoskeletal systems. Therefore, acute agitation needs to be addressed, as it may be an independent risk factor for excess morbidity.
Nonpharmacologic measures are preferred for management of chronic recurring agitated behaviors, but these interventions may have limited efficacy, especially during episodes of acute exacerbation. There has been increasing concern about cerebrovascular morbidity and mortality in patients with dementia-related psychosis associated with chronic use of atypical antipsychotics in studies over 6- to 26-week periods.1 The risk of cerebrovascular adverse events (AEs) has merited warning in product labels2, 3, 4, 5, 6 and these medications are not approved for treatment of dementia-related psychosis. Retrospective cohort studies have suggested that conventional and atypical antipsychotics do not differ significantly in their risk of cerebrovascular AEs7, 8 or mortality9 in older adults.
Ongoing debate regarding a limited therapeutic role for atypical antipsychotics in long-term care remains. But few well-controlled studies with objective criteria assess acute use of atypical antipsychotics in dementia patients. Therefore, clinicians cannot weight the benefit/risk of intermittent, time-limited treatment using intramuscular (IM) formulations that have faster onset of action than oral medication.
The partial D2-receptor agonist aripiprazole is pharmacologically distinct from other atypical agents.10, 11 Three Phase III studies have shown the safety and efficacy of oral aripiprazole in the treatment of psychotic and behavioral symptoms in elderly patients with Alzheimer's dementia (AD).12, 13, 14 Other studies in patients with psychiatric disorders such as schizophrenia and bipolar disorder have shown efficacy of IM aripiprazole for treatment of agitation with low incidence of oversedation and extrapyramidal symptoms (EPS).15, 16, 17
The purpose of this study (Study CN138–131) was to evaluate the tolerability and preliminary efficacy of IM aripiprazole in patients with acute agitation associated with AD, vascular, or mixed dementia residing in healthcare facilities.
Patients and Methods
The study was conducted in accordance with generally accepted standards for the protection of patient safety and welfare and in compliance with Good Clinical Practice, and the principles of the Declaration of Helsinki and its amendments. Written informed consent was given by the legally authorized representatives of the healthcare facility residents because of the residents' levels of dementia.
Patients
The study enrolled male and female patients (aged 55 to 95 years diagnosed with AD, vascular, or mixed dementia,18 residing in healthcare facilities) who manifested moderate-to severe acute exacerbations of agitated behaviors defined as Positive and Negative Syndrome Scale (PANSS) Excited Component (PEC) score ≥15 and ≤32 with ≥1 of the 5 items with a score ≥4. Subjects with other major DSM-IV Axis I psychiatric disorders based on clinical examination were excluded, as were those with a history of neuroleptic malignant syndrome, seizure, abnormal electroencephalogram not attributable to AD or vascular dementia, severe head trauma or stroke, and compulsorily detained patients. Included patients had to be able to comprehend and satisfactorily comply with the protocol requirements (including ambulatory 12-lead electrocardiogram monitor).
Study Design
This double-blind, placebo-controlled tolerability study was conducted at 16 centers in the United States (17 December 2003 to 25 March 2005). Eligible patients were enrolled in 3 sequential cohorts, each beginning with 15 patients, and randomized (4:1) to treatment with an injection of IM aripiprazole or IM placebo, followed by a second injection 2 hours later. Patients were clinically observed over 24 hours.
Patients in Cohort 1 were randomized to 2 injections of IM aripiprazole 2.5 mg (0.33 mL of a 7.5-mg/mL solution; actual dose 2.475 mg) or IM placebo. In Cohort 2, patients were randomized to 2 injections of IM aripiprazole 5 mg (0.67 mL of a 7.5-mg/mL solution; actual dose 5.025 mg) or IM placebo. Methods for Cohort 3 were the same as for Cohorts 1 and 2, except that the first injection of IM aripiprazole was 10 mg (1.3 mL of a 7.5-mg/mL solution; actual dose 9.75 mg) and the second was 5 mg (0.67 mL of a 7.5-mg/mL solution; actual dose 5.025 mg). Patients received the first injection within 1 hour of baseline assessments and the second injection 2 hours after the first injection.
After 15 patients had completed each in each cohort, an interim safety analysis was performed on the blinded safety data before enrolling additional patients.
Concomitant medications that might have interfered with assessments of efficacy or safety were prohibited within 4 hours before baseline assessment and during the 4-hour efficacy evaluation phase after baseline.
Safety and Efficacy Assessments
Safety assessments included reports of AEs and changes in electrocardiograms, vital signs, laboratory tests, and the Simpson−Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), and Mini Mental State Examination (MMSE) rating scales. Patients were continuously monitored with a digital ambulatory 12-lead monitor from 2 hours before to 22 hours after the first injection, as well as intermittently with standard 12-lead electrocardiogram tracings. Efficacy analyses were performed for the PEC, Agitation–Calmness Evaluation Scale (ACES), Clinical Global Impressions–Severity of Illness (CGI-S), and Clinical Global Impressions–Improvement (CGI-I) rating scales.
Statistical Analyses
The safety sample included all randomized patients who received 1 dose or more of study medication. The efficacy sample comprised all patients in the safety sample who had 1 or more postrandomization efficacy evaluation and a corresponding baseline value (not applicable to CGI-I). Efficacy analyses were performed using SAS statistical software, version 6.12 or higher (SAS Institute, Inc., Cary, NC).
Results
Cohort Enrollment
The dose range of 5 to 15 mg of IM aripiprazole was satisfactorily tolerated by all 3 cohorts. Interim evaluation of blinded safety data revealed a slight increase in the incidence of somnolence in the 15-mg cohort. Consequently, additional enrollment was continued using the IM aripiprazole 10-mg dose versus IM placebo cohort.
Patient Disposition and Baseline Characteristics
Of the 150 patients enrolled, 129 were randomized to IM treatment: 26 to placebo, 12 to aripiprazole 5 mg (Cohort 1), 78 to aripiprazole 10 mg (Cohort 2), and 13 to aripiprazole 15 mg (Cohort 3). In total, 127 patients (98%) completed the study. One discontinued (IM aripiprazole 15-mg group) due to an AE (femoral neck fracture resulting from a fall on a wet floor) and one (IM placebo group) no longer met study criteria. Patient baseline demographics and characteristics are given in Table 1.
Table 1. Patient Demographics and Baseline Characteristics
| IM Placebo (Total from 3 Cohorts) | IM Aripiprazole 5 mg (Cohort 1) | IM Aripiprazole 10 mg (Cohort 2) | IM Aripiprazole 15 mg (Cohort 3) | IM Aripiprazole (Total from 3 Cohorts) | |
|---|---|---|---|---|---|
| N | 26 | 12 | 78 | 13 | 103 |
| Mean ± SD age, y | 79.5 ± 7.8 | 80.2 ± 5.4 | 80.0 ± 10.3 | 79.9 ± 6.0 | 80.0 ± 9.3 |
| Male/female, n (%) | 10/16 (38/62) | 4/8(33/67) | 28/50(36/64) | 4/9(31/69) | 36/67(35/65) |
| Race, n (%) | |||||
| White | 22(85) | 9(75) | 61(78) | 13(100) | 83(81) |
| Black/African | 4(15) | 3(25) | 17(22) | 0 | 20(19) |
| American | |||||
| Ethnicity, n (%) | |||||
| Hispanic/Latino | 6(23) | 3(25) | 6(8) | 1(8) | 10(10) |
| Not Hispanic/Latino | 20(77) | 9(75) | 72(92) | 12(92) | 93(90) |
| Underlying diagnosis, n (%) | |||||
| Alzheimer's dementia | 22(85) | 9(75) | 61(78) | 10(77) | 80(78) |
| Mixed dementia | 2(8) | 2(17) | 12(15) | 1(8) | 15(15) |
| Vascular dementia | 2(8) | 1(8) | 5(6) | 2(15) | 8(8) |
| Mean ± SD age at diagnosis, y | 75.7 ± 8.2 | 76.3 ± 4.6 | 76.3 ± 11.0 | 76.7 ± 6.5 | 76.4 ± 9.9 |
| Mean ± SD PEC Total score | 20.0 ± 3.7 | 21.7 ± 3.9 | 20.6 ± 3.7 | 20.8 ± 3.3 | 20.7 ± 3.7 |
| Mean ± SD ACES score | 2.0 ± 0.5 | 1.9 ± 0.5 | 2.1 ± 0.6 | 2.1 ± 0.8 | 2.1 ± 0.6 |
| Mean ± SD CGI-S score | 4.3 ± 0.5 | 4.3 ± 0.5 | 4.3 ± 0.7 | 4.5 ± 0.9 | 4.4 ± 0.7 |
Concomitant medication use was generally comparable in all treatment groups, but placebo-treated patients required increased use of rescue benzodiazepine, indicating a clinically greater need for additional anxiolytic medication following the 4-hour efficacy interval of the study (Table 2). The most commonly used concomitant medications for all treatment groups were nonopioid analgesics and antipyretics.
Table 2. Use of Concomitant Medication During the Study
| IM Placebo (Total from 3 Cohorts) | IM Aripiprazole 5 mg (Cohort 1) | IM Aripiprazole 10 mg (Cohort 2) | IM Aripiprazole 15 mg (Cohort 3) | IM Aripiprazole (Total from 3 Cohorts) | |
|---|---|---|---|---|---|
| N | 25 | 12 | 76 | 15 | 103 |
| Any CNS medication, n (%) | 23(92.0) | 11(91.7) | 63(82.9) | 13(86.7) | 87(84.5) |
| Anticholinergic | 0 | 0 | 0 | 1(6.7) | 1(1.0) |
| Antidepressant | 10(40.0) | 5(41.7) | 34(44.7) | 5(33.3) | 44(42.7) |
| Antiepileptic | 3(12.0) | 2(16.7) | 7(9.3) | 2(13.3) | 11(10.7) |
| Antipsychotic | 0 | 0 | 1(1.3) | 1(6.7) | 2(1.9) |
| Anxiolytic | 9(36.0) | 3(25.0) | 10(13.2) | 2(13.3) | 15(14.6) |
| Dopaminergic | 4(16.0) | 0 | 9(11.8) | 2(13.3) | 11(10.7) |
| Hypnotic and sedative | 1(4.0) | 0 | 2(2.6) | 0 | 2(1.9) |
| Opioid | 2(8.0) | 1(8.3) | 6(7.9) | 1(6.7) | 8(7.8) |
| Other analgesic and antipyretic | 13(52.0) | 5(41.7) | 46(60.5) | 8(53.3) | 59(57.3) |
| Parasympathomimetic | 2(8.0) | 0 | 4(5.3) | 2(13.3) | 6(5.8) |
| Psychostimulant | 11(44.0) | 4(33.3) | 20(26.3) | 4(26.7) | 28(27.2) |
| Any EPS medication, n (%) | 0 | 0 | 1(1.3) | 1(6.7) | 2(1.9) |
| Amantadine | 0 | 0 | 1(1.3) | 0 | 1(1.0) |
| Trihexyphenidyl | 0 | 0 | 0 | 1(6.7) | 1(1.0) |
Safety and Tolerability Assessments
All 3 IM aripiprazole doses were generally well tolerated (Table 3). In most patients (≥91%), AEs were mild/moderate in severity. The only discontinuation was associated with an environmental hazard (wet floor).
Table 3. Incidence of Treatment-Emergent Adverse Events That Occurred in at Least 5% of Patients in any Treatment Group During the Study (Safety Sample)
| IM Placebo (Total from 3 Cohorts) | IM Aripiprazole 5 mg (Cohort 1) | IM Aripiprazole 10 mg (Cohort 2) | IM Aripiprazole 15 mg (Cohort 3) | IM Aripiprazole (Total from 3 Cohorts) | |
|---|---|---|---|---|---|
| N | 25 | 12 | 76 | 15 | 103 |
| During the whole study, n (%) | |||||
| Any adverse event | 8(32.0) | 6(50.0) | 41(54.0) | 9(60.0) | 56(54.4) |
| Somnolence | 2(8.0) | 2(16.7) | 30(39.5) | 5(33.3) | 37(35.9) |
| Dementia | 0 | 3(25.0) | 0 | 0 | 3(2.9) |
| Lethargy | 0 | 0 | 0 | 1(6.7) | 1(1.0) |
| Vomiting | 0 | 1(8.3) | 3(4.0) | 0 | 4(3.9) |
| Pyrexia | 0 | 0 | 0 | 1(6.7) | 1(1.0) |
| Skin laceration | 2(8.0) | 0 | 1(1.3) | 1(6.7) | 2(1.9) |
| Fall | 1(4.0) | 0 | 0 | 1(6.7) | 1(1.0) |
| Femoral neck fracture | 0 | 0 | 0 | 1(6.7) | 1(1.0) |
| Electrocardiogram change | 0 | 0 | 0 | 1(6.7) | 1(1.0) |
| Irregular heart rate | 0 | 0 | 0 | 1(6.7) | 1(1.0) |
| Insomnia | 0 | 0 | 2(2.6) | 1(6.7) | 3(2.9) |
| Agitation | 2(8.0) | 0 | 1(1.3) | 0 | 1(1.0) |
| First onset/increased severity after the second injection, n (%) | |||||
| Any adverse event | 5(21.7) | 5(45.5) | 23(31.1) | 4(30.8) | 32(32.7) |
| Somnolence | 0 | 1(9.1) | 8(10.81) | 1(7.7) | 10(10.2) |
| Dementia | 0 | 3(27.3) | 0 | 0 | 3(3.1) |
| Lethargy | 0 | 0 | 0 | 1(7.7) | 1(1.0) |
| Vomiting | 0 | 1(9.1) | 3(4.1) | 0 | 4(4.1) |
| Skin laceration | 2(8.7) | 0 | 1(1.4) | 1(7.7) | 2(2.0) |
| Fall | 1(4.4) | 0 | 0 | 1(7.7) | 1(1.0) |
| Femoral neck fracture | 0 | 0 | 0 | 1(7.7) | 1(1.0) |
| Insomnia | 0 | 0 | 2(2.7) | 1(7.7) | 3(3.1) |
| Agitation | 2(8.7) | 0 | 1(1.4) | 0 | 1(1.0) |
Somnolence was the only treatment-emergent AE with a higher incidence versus placebo across all 3 IM aripiprazole cohorts (Table 3). All cases of somnolence were mild/moderate in severity. The incidence of sedation was low, occurring only once (1.3%) with IM aripiprazole 10 mg and once (4%) with IM placebo.
As the only death occurred 24 days after treatment (IM aripiprazole 10-mg group), there was no reasonable link to study medication. A total of 12 patients experienced a serious AE: 2 (8.0%) with IM placebo, 3 (25.0%) with IM aripiprazole 5 mg, 6 (7.9%) with IM aripiprazole 10 mg, and 1 (6.7%) with IM aripiprazole 15 mg. Most serious AEs were related to the patient's known underlying illnesses, so were judged unlikely to be treatment-related. The only cerebrovascular AE (acute stroke) occurred 16 days after treatment (IM aripiprazole 10-mg group) and therefore was judged unlikely to be treatment-related. No patient experienced EPS. No IM aripiprazole-treated patient discontinued because of any laboratory, vital sign or QTc abnormality. There were no clinically significant changes in either vital signs or electrocardiograms.
Mean decreases from baseline in the SAS Total score were observed at most time points with IM aripiprazole and IM placebo (Figure 1). Mean decreases from baseline in the BARS scores were observed at all time points with IM aripiprazole 10 mg (–0.1 ± 0.0 at all time points), and at 2 hours (–0.1 ± 0.1) and 4 hours (–0.1 ± 0.1) with IM aripiprazole 15 mg.
Fig. 1.
Mean change in Simpson−Angus Scale Total score from baseline during intramuscular treatment. The Simpson−Angus Scale is a 10-item scale rated from 1 (normal) to 5 (worst), with a negative change on the Total score (scale 10–50) indicating a reduction in extrapyramidal symptoms.
Mean improvements from baseline in MMSE Total scores (scale 0–30) were observed at 24 hours with IM placebo (+0.5 ± 0.6 from 9.6 ± 1.5), IM aripiprazole 10 mg (+0.3 ± 0.3 from 10.1 ± 1.0) and IM aripiprazole 15 mg (+0.7 ± 0.3 from 5.3 ± 1.3), but not IM aripiprazole 5 mg (–0.9 ± 0.5 from 9.4 ± 2.3) (last observation carried forward [LOCF]).
Desired Outcome Effects
Mean decreases from baseline in PEC scores were greater with all 3 IM aripiprazole dose groups versus IM placebo at 30 minutes (Figure 2, A) and continued to be greater throughout the 24-hour study with only 2 exceptions (6 and 24 hours with IM aripiprazole 5 mg).
Fig. 2.
Efficacy outcomes during intramuscular treatment. (A) Mean change in Positive and Negative Syndrome Scale Excited Component (PEC) score from baseline, (B) mean Clinical Global Impression–Improvement (CGI-I) score, (C) mean change in Agitation–Calmness Evaluation Scale (ACES) score from baseline (last observation carried forward data set). The PEC score consists of 5 PANSS items (hostility, lack of cooperation, excitement, poor impulse control, tension), each rated on a scale of 1 (absent) to 7 (extreme). A negative change from baseline in the PEC score (scale 5–35) signifies improvement. The CGI-I score is measured on a scale from 1 (very much improved) to 7 (very much worse), where a lower score signifies greater improvement. The ACES score is assessed on a scale of 1 (marked agitation) to 9 (unarousable); a score of 4 indicates normal; a positive change from baseline signifies improvement.
Mean CGI-I score was lower for all 3 IM aripiprazole dose groups versus IM placebo at most time points (Figure 2, B). Similarly, mean changes in CGI-S scores from baseline were equal to or greater than IM placebo in the 3 IM aripiprazole groups at most time points (except 6 and 24 hours with IM aripiprazole 5 mg, and 30 and 60 minutes with IM aripiprazole 15 mg; data not shown).
Mean change from baseline in the ACES score was equal to or greater than IM placebo at 0.5, 3, 4, and 12 hours with IM aripiprazole 5 mg; and at all time points with IM aripiprazole 10 mg and 15 mg (Figure 2, C). Approaching normal, the ACES score increased by a mean of 1.7 ± 0.2 at 2 hours after the first injection and 1.3 ± 0.1 at 24 hours, from 2.1 ± 0.1 at baseline in IM aripiprazole-treated patients (all doses). With IM placebo, ACES scores increased from 2.0 ± 0.1 at baseline by 1.7 ± 0.4 at 2 hours and 0.8 ± 0.1 at 24 hours. Of the 103 IM aripiprazole-treated patients, 39 (38%) experienced an ACES score of 8 at any time point versus 8 (32%) of 25 IM placebo-treated patients, of which only 10 events (IM aripiprazole 10 mg, n = 8; IM placebo, n = 2) occurred before the second injection. A total of 2 (1.9%) IM aripiprazole-treated patients experienced an ACES score of 9 during IM treatment (both in the IM aripiprazole 10-mg group) versus none of the IM placebo-treated patients.
Discussion
In elderly patients with agitation associated with Alzheimer's, vascular, or mixed dementia, IM aripiprazole in total daily doses of 5 to 15 mg was well tolerated and associated with improvements in efficacy measures when compared with IM placebo.
Since this study did not identify a maximum tolerated dose for this patient population, the 10-mg dose would be expected to be preferable to the 15-mg dose due to its similar safety and efficacy.
Somnolence was the only treatment-emergent AE reported at a higher incidence than IM placebo across all IM aripiprazole groups, but this was mild/moderate in severity, and no patient discontinued because of it. The ACES—a single-item scale designed to assess reduction in agitation—differentiates between the states of agitation, calmness, and sleep.19, 20 The incidence of ACES scores of 8 (deep sleep) or 9 (unarousable) was analyzed as a categorical measure of oversedation. That few IM aripiprazole-treated patients experienced ACES scores of 8 or 9 in the first 2 hours suggests this treatment resulted in a calming effect with a low risk for oversedation.
Use of the PEC scale in this study provided objective and valid criteria to assess the success of the treatment of agitation. This is of particular importance in the treatment of elderly patients with dementia, who are particularly sensitive to AEs. The PEC is a validated psychiatric research scale21 that was previously used in an IM olanzapine study of patients with agitation associated with dementia.20 The PEC reliably measures symptoms that are readily recognizable and relevant because of their direct effects on clinical practice. Examples of such scenarios would be uncooperative behaviors that result in suboptimal adherence, excitable and hostile behaviors that increase caregiver burden, and tension that increases patient discomfort. In addition, poor impulse control can make the outcome of treatment unpredictable.
In general, improvements on the PEC, CGI-I, CGI-S, and ACES rating scales were greater with IM aripiprazole versus IM placebo. This suggests potential efficacy of IM aripiprazole 10 mg and 15 mg in this target population. Over the 24-hour study duration, the apparent perturbation in the efficacy rating scale scores at 12 hours (Figure 2) likely reflects most patients being asleep during the night-time period.
The significant improvements in the PEC score observed with IM aripiprazole versus placebo and the overall tolerability profile provide evidence for a favorable benefit:risk ratio of IM aripiprazole in acute treatment of agitation associated with dementia.
Conclusions
A total of 10 mg or 15 mg of IM aripiprazole administered in divided doses was safe and well tolerated for the treatment of agitation associated with Alzheimer's, vascular, or mixed dementia.
Acknowledgments
We acknowledge Kimberly Gentile and Lori Rawlings, RN, for their leadership roles in the study.
We thank all of the study's principal investigators: Marc Edward Agronin, MD (Miami Jewish Home, Miami, FL); Edward Burdick, MD (Behavioral Clinical Research, Inc, C/O Segal Institute For Clinical Research, North Miami, FL); Bernadette D'Souza, MD (East Medical Plaza, Dayton, OH); Robert Dolgoff, MD (Berkeley Therapy Institute, Berkeley, CA); Jose Gamez, MD (Berma Research Group, Hialeah, FL); Paul Kettl, MD (Penn State College Of Medicine, Hershey, PA); Melinda Lantz, MD (The Jewish Home & Hospital, New York, NY); Michael Levy, MD (Behavioral Medical Research of Staten Island, Staten Island, NY); David E Linden, MD (Linden Research Consultants, LLC, Oklahoma City, OK); Mary Jane Norman, MD (Pivotal Research Centers, Midvale, UT); Michael Plopper, MD (Sharp Mesa Vista Hospital, San Diego, CA); Stephen Rappaport, MD (Agewell Health, Indianapolis, IN); Ralph Richter, MD (Clinical Pharmaceutical Trials, Inc, Tulsa, OK); Alan Siegal, MD (Center For Geriatric & Adult Psychiatry, Hamden, CT); Kenneth Sokolski, MD (Clinical Innovation, Inc, Santa Ana, CA); Jaron Winston, MD (Senior Adults Specialty Research, Austin, TX).
All people who contributed significantly to the study have been acknowledged.
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This study was supported by Bristol-Myers Squibb (Princeton, NJ) and Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan). Editorial support for the preparation of this manuscript was provided by Ogilvy Healthworld Medical Education; funding was provided by Bristol-Myers Squibb.
PII: S1525-8610(08)00253-3
doi:10.1016/j.jamda.2008.06.006
© 2009 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.
