First Report®

AMDA--Dedicated to Long Term Care Medicine 2013 Annual Meeting

March 27-31, 2013; Washington, DC
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PRODUCT THEATER

Examining Treatment of Xenazine for Huntington’s Disease Patients With Chorea

Huntington’s disease (HD) is a relatively rare neurodegenerative, genetic disorder characterized by motor, psychiatric, and cognitive symptoms. The disorder is caused by an expansion of a repeating CAG triplet series in the huntingtin gene on chromosome 4.

Approximately 25,000 individuals in the United States are symptomatic. The average age of becoming symptomatic is 30 to 50 years. Death usually occurs 10 to 30 years after onset. Diagnosis of adult-onset HD is usually made upon the start of chorea (abnormal involuntary movements). Because of the degenerative nature of HD, individuals may require long-term care (LTC). However, identifying an LTC facility to meet patients’ needs is a challenge.

The FDA-approved Xenazine (tetrabenazine) for the treatment of chorea associated with HD in August 2008. Because Xenazine is not stocked in retail pharmacies, it is available through a treatment form and specialty pharmacy distribution.

In a product theater at the AMDA conference, Adam Rosenblatt, MD, professor of psychiatry and neurology, director of geriatric psychiatry at Virginia Commonwealth University, Richmond, discussed chorea associated with HD and therapy with Xenazine. Clinical Geriatrics® (CG) had the opportunity to interview Rosenblatt about HD, management of the disease in LTC, and treatment considerations.

CG: How many LTC facilities are familiar with HD?
Dr. Rosenblatt:
A majority of HD patients at the end of their life will end up in LTC. Many LTC facilities do not have much experience with HD patients. While it is not a typical experience, I have known of LTC facilities turning away HD patients. There are a small number of LTC facilities that have enough experience with HD patients, and they are the go-to places. When there is a close relationship between the expert [eg, physician] and the LTC facility and good communication between all involved parties, these placements are most successful.

How do patients with HD differ demographically from the average LTC resident?
They are younger than the average patient admitted into an LTC facility; can have more severe movement, psychiatric, and/or behavioral disorders; and lack serious comorbid medical diagnoses on admission.

What are some of the challenges LTC facilities face in caring for these patients?
Patients with HD are at risk for other psychiatric disorders, including depression. Since the condition is progressive, patients are at risk of falls and lack insight that they could fall. They need help to ambulate. They have trouble eating by mouth because of the involuntary movements, making it difficult for them to maintain their weight. When movement becomes extravagant, they become physically hard to manage in LTC settings. Some patients require specialized reclining chairs or beds that are low to the ground.

What are the hallmark symptoms of HD?
Symptoms can vary between individuals. It manifests as a triad of motor, cognitive, and psychiatric symptoms. Motor symptoms include involuntary movement (chorea) and impairment of voluntary movements. Cognitive function is characterized by a reduction in speed and flexibility of mental processing and difficulty planning and prioritizing. With psychiatric symptoms, the most common diagnosis is depression, found in 40% of cases. While personality changes can be subtle, patients can exhibit impulsivity, apathy, irritability, and obsessionality.

When is a diagnosis of adult-onset HD usually made?
It is not black and white. In adults, the condition usually presents as cognitive or psychiatric, although some patients do exhibit abnormal movements. Often, the patient is unaware of it and family members or physicians may be the first to notice the symptoms.

Chorea affects about 90% of individuals with HD at some stage in their illness. How does it progress?
It can present at first subtly in the hands and feet, but it may include neck, shoulder, trunk, and leg movements as it progresses. As movements eventually occur throughout the body, it can become quite disabling. In time, chorea may plateau and decline, or continue to worsen.

How is chorea severity assessed?
Various scales can be used. The Unified Huntington’s Disease Rating Scale (UHDRS) is often used in research. You score patients 0 to 4 in different parts of the body; the total score ranges from 0 to 28. It is useful if you are going to treat a patient. I use the scale to rate the patient before starting treatment and again a few weeks after starting treatment to see if there is a difference.

Is there any treatment available to slow, stop, or reverse the progression of HD?
Currently, there is no treatment proven to alter the progression of the disease. This is not to say that you cannot alter the outcome, as you can still intervene in fundamental areas to improve quality of life. For example, if a patient is severely depressed, you can treat the depression.

How does Xenazine improve chorea?
The precise mechanism by which Xenazine exerts its antichorea effects is unknown, but it is thought to be related to the agent’s effect as a reversible depletor of monoamines from nerve terminals. Vesicular monamine transporter subtype 2 (VMAT2) transports and concentrates monamines (including dopamine) into presynaptic storage vesicles. Xenazine reversibly binds to VMAT2 and reduces uptake of dopamine into synaptic vesicles.

What did the pivotal trial of Xenazine show in total chorea score (TCS) and how long did improvement last versus placebo?
The efficacy of Xenazine was demonstrated in a randomized, double-blind, placebo-controlled, multicenter trial. A total of 84 ambulatory patients with HD were randomly assigned to receive Xenazine (n=54) or placebo (n=30) for 12 weeks. The primary end point was the reduction in TCS using the UHDRS. A reduction of 3 or more was defined as clinically meaningful per the study protocol. The results showed that 69% of patients had a statistically significant improvement in TCS compared with 23% of patients receiving placebo (P<.0001). Significant improvement in chorea was observed by week 3 and improvement continued throughout the trial. TCS returned to baseline levels during the washout period.

Xenazine carries a boxed warning for increased risk of depression and suicide. What steps should clinicians take when prescribing Xenazine to patients who already have or are at risk for depression and suicidal thoughts?
Clinicians have to balance the risk of suicide and depression with the benefits of Xenazine. I probably would not give Xenazine to someone who has tried to kill himself or herself, is in a depressive state, or has no support system. In LTC, there is a high level of supervision; however, these patients generally do not communicate well and cannot express they are depressed. Therefore, staff needs to closely watch for warning signs in these patients, including withdrawal and lack of sleep.

What is the recommended dosing for Xenazine?
There is no single target dose for Xenazine. Dosing should be individualized based on patient response. The starting dose is 12.5 mg per day. After 1 week, the dose should be increased to 25 mg per day given as 12.5 mg twice daily. Xenazine should be titrated up slowly at a weekly interval of 12.5 mg daily until a patient experiences clinical effect or an adverse event occurs that is not tolerated. Dosing above 100 mg daily is not recommended for any patient.

This product theater was sponsored by Lundbeck.
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Tackling the Clostridium difficile Dilemma in Nursing Homes

Long-term care (LTC) providers nationwide are facing increasing incidences of Clostridium difficile infection (CDI) among their residents, and it is currently the most common infectious cause of acute diarrhea in this setting. In addition, more severe infections are being observed, making prevention crucial. During an educational session at the AMDA conference, presenters discussed various preventive and treatment strategies for CDI, including the proper use of antibiotics and following recommendations set forth by the Society for Healthcare Epidemiology (SHEA) and Infectious Diseases Society of America (IDSA). The role of probiotics and antibiotic stewardship programs were also reviewed.

Preventing and Managing CDI
The Centers for Disease Control and Prevention (CDC) report that antibiotics are the most commonly prescribed medication in LTC settings, with up to 70% of LTC residents receiving an antibiotic each year. Presenter Amy Mathers, MD, assistant professor, Division of Infectious Diseases and International Health, University of Virginia, who discussed the prevention of CDI, noted that CDI most commonly occurs after antibiotic use. During the session, one study was discussed that showed that 33% of LTC residents had C difficile in their stool after taking antibiotics, even if they did not develop diarrhea.

“Learning how antibiotics are used in your facility is important in preventing C difficile,” Mathers told attendees. She noted that antibiotics are often misused in LTC settings, such as by being given when they are not needed, continued when they are no longer necessary, and given at the wrong dose.

When CDI infections occur despite best efforts to prevent them, appropriate and timely treatment is essential to prevent morbidity and mortality. Mathers recommended that the SHEA and IDSA 2010 practice guidelines for C difficile be implemented. These guidelines make the following treatment recommendations:

•  For an initial episode of mild-to-moderate CDI, prescribe oral metronidazone 500 mg three times daily for 10 to 14 days.

•  For severe CDI, prescribe oral vancomycin 125 mg four times daily for 10 to 14 days.

•  For complicated or severe CDI, prescribe oral vancomycin (or per rectum if ileus is present) with or without intravenously administered metronidazole. The oral vancomycin dosage is 500 mg four times a day and the rectal dosage is 500 mg in approximately 100 mL normal saline every 6 hours as a retention enema. If metronidazole is given, the dose is 500 mg intravenously every 8 hours.

Role of Probiotics
Probiotics may offer an alternative for preventing and possibly treating CDI, said Glynis Kolling, PhD, microbiologist, Division of Infectious Diseases and International Health, University of Virginia, noting that probiotics can help restore normal flora that are altered with antibiotics. She said studies have shown that probiotics can help prevent antibiotic-associated diarrhea and therefore may be beneficial in the setting of CDI.

Although the SHEA and IDSA 2010 practice guidelines for C difficile do not recommend the use probiotics to prevent primary CDI because the data to support this approach have been limited and there is a potential risk of bloodstream infection, Kolling noted that the new guidelines that are targeted for release later this year may include an updated recommendation on probiotics.

Probiotics have an excellent overall safety record, but Kollings and Mathers warned that they should be used with caution in patients with an immune deficiency and are contraindicated in patients with an impaired epithelial barrier, such as a diarrheal illness or intestinal inflammation.

“Probiotics may not be for everyone. You have to determine if probiotics will benefit the patient,” concluded Mathers.

Antimicrobial Stewardship
C difficile
is a community infection that does not stay confined to the hospital or nursing home, warned presenter Laurie Archbald-Pannone, MD, MPH, assistant professor, Department of Internal Medicine, University of Virginia. Because it follows patients as they move in and out of any facility, antibiotic stewardship programs are at the forefront of preventing its spread. Her colleague Mathers defined anti-biotic stewardship as “selecting the most appropriate drug at its optimal dose and duration of therapy to eradicate an infection while minimizing toxicity and impact on selective pressure [ie, any cause that reduces reproductive success in a proportion of a population].” She noted that medical directors are responsible for fostering stewardship. These healthcare professionals should routinely review facility microbiology and antibiograms for local resistance trends, implement policies for prudent antimicrobial prescribing, and put in place nursing protocols for monitoring.

In addition, before any antibiotic is prescribed, Mathers recommended that all healthcare providers follow the CDC’s Get Smart for Healthcare (www.cdc.gov/getsmart/healthcare/index.html) program, which includes the following three-step process aimed at preventing inappropriate antibiotic prescribing:

1. Ensure all antibiotic orders include dose, duration, and indication.

2. When placing orders, make certain that they include laboratory cultures.

3. When the culture results come back in 24 to 48 hours, take an “antibiotic time-out” and reassess therapy.—Eileen Koutnik-Fotopoulos

The presenters of this educational session reported no relevant financial relationships.
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The High Cost of Major Bleeding in Patients With Nonvalvular Atrial Fibrillation

A retrospective analysis of healthcare claims for commercially insured and Medicare Advantage enrollees found that patients with nonvalvular atrial fibrillation who had major bleeding had substantially higher healthcare costs and more days in the hospital compared with those who had less severe bleeding. Results of the analysis were presented at the ACC meeting during a poster session.

Approximately 5 million adults in the United States have atrial fibrillation, a common cardiac rhythm disorder that is associated with a risk of bleeding, which can lead to higher costs, according to the authors. This study examined the Optum Research Database, which contains health plan member data, including enrollment information and inpatient, outpatient, and pharmacy claims. The authors obtained dates of death using the Social Security Death Master File.

Patients were included if they were 18 years of age or older and had two or more inpatient, emergency department, or ambulatory visits with a primary or secondary atrial fibrillation diagnosis on dates separated by at least 30 days between January 1, 2005 and June 30, 2009. They had to be continuously enrolled in the health plan for at least 1 year, and they could not have evidence of cardiac valvular disease. They were followed until they died, stopped enrollment in the plan, or made it to June 30, 2010—whichever time came first. The analysis included 48,260 patients. The mean age was 67.3 years, 71.2% of patients had commercial insurance, 62.2% were men, and 62.9% had hypertension. The mean length of follow-up was 802 days.

The authors found that 16,409 patients had a bleeding event. The mean cost for major bleeding events (n=6684) was $16,830, while the mean cost for serious nonmajor bleeding events (n=2017) was $1822, and the mean cost for minor bleeding events (n=7708) was $611. The mean duration for the events was 8 days: 15 days for major bleeding, 3 days for serious nonmajor bleeding, and 3 days for minor bleeding.

The mean daily cost for patients without bleeding was $33.67 compared with $48.28 for those who experienced bleeding. In the major bleeding group, the mean daily cost was $63.38 compared with $47.21 for those who had serious nonmajor bleeding and $37.96 for those with minor bleeding.

The mean duration of the postbleeding period was 523 days for patients with major bleeding, 583 days for patients with serious nonmajor bleeding, and 646 days for patients with minor bleeding. The authors noted a few limitations, including that the study relied on diagnostic codes from medical claims, which could have contained coding errors. They also noted that the results might be limited to patients with commercial or Medicare Advantage coverage and not to those with other types of coverage or the uninsured population. In addition, because the study was a descriptive, unadjusted cost analysis, patient factors other than bleeding events could have contributed to the high costs.—Tim Casey

This study was supported by Bristol-Myers Squibb and Pfizer Inc.
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Ranolazine for Type 2 Diabetes, Coronary Artery Disease, and Chronic Stable Angina

Patients with type 2 diabetes, coronary artery disease, and chronic stable angina who took ranolazine had fewer angina episodes and fewer sublingual nitroglycerin dosages compared with a group receiving placebo, according to a randomized, double-blind, placebo-controlled study. Ranolazine is FDA-approved to treat chronic angina as a first-line therapy and as an add-on therapy when symptoms are not relieved using other antianginal drugs. Mikhail Kosiborod, MD, the study’s lead author, presented the data in a late-breaking clinical trial session at the ACC meeting. Results were simultaneously published online in the Journal of the American College of Cardiology (10.1016/j.jacc.2013.02.011).

Between weeks 2 and 8 of treatment, the mean angina frequency was 3.8 episodes per week in the ranolazine group compared with 4.3 episodes per week in the placebo group (P=.008). During that same time period, the mean number of sublingual nitroglycerin doses per week was 1.7 in the ranolazine group and 2.1 in the placebo group (P=.003). Kosiborod said 8 million people in the United States have angina, which is associated with a negative impact on health status and quality of life as well as repeat hospitalizations and high costs. He also said patients with diabetes are at an increased risk of coronary artery disease and have a greater angina burden.

The TERISA (Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable Angina) study recruited patients at 105 sites in 14 countries and was the first to test the antianginal effect of ranolazine in patients with diabetes. All patients had experienced symptoms despite receiving one or two antianginal medications. The authors collected data on angina frequency and sublingual nitroglycerin use on a daily basis using an electronic diary tool. During the study, 98% of patients added the data in their diary daily.

The trial began with a 4-week, single-blind, run-in phase during which all patients received placebo to establish the baseline angina frequency and to ensure patients were compliant with the study medication and with an electronic symptom diary, according to Kosiborod. The 949 patients were then randomized to receive 1000 mg ranolazine (n=473) or placebo (n=476) twice daily for 8 weeks.

The groups were well balanced at baseline. The mean age was approximately 64 years, 61% were men, and 99% were white. The mean duration of diabetes was approximately
7.5 years, the mean HbA1c level was 7.3%, and 93% of patients were taking glucose-lowering medications. More than 80% of patients were taking concomitant statins or antiplatelet agents.

A subgroup analysis found that among patients recruited from Russia, Ukraine, and Belarus, there was no significant difference in mean angina frequency: 4.1 episodes per week in the ranolazine group and 4.3 episodes per week in the placebo group (P=.31). However, there was a significant difference among patients recruited from the other 11 countries, with patients taking ranolazine having a mean angina frequency of 3.1 episodes per week compared with 4.1 episodes per week in the placebo group (P=.002).

In addition, according to an exploratory, post hoc analysis, the benefit in angina frequency favoring ranolazine was significant in patients regardless of their HbA1c level, although the drug’s effect was more profound in patients with a higher HbA1c level at baseline. Further, there was no significant difference in serious adverse events, which occurred in 3.4% of patients in the ranolazine group and 4.2% of patients in the placebo group (P=.51). Kosiborod added nonserious adverse events, such as dizziness, nausea, and constipation, were more frequent in the ranolazine group, but they were “overall infrequent.”—Tim Casey

This study was funded by Gilead Sciences, Inc.