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LTC Bulletin Board - December 2012
FDA News
FDA Approves Xeljanz for Treatment of Rheumatoid Arthritis
On November 6, 2012, the FDA approved Xeljanz (tofacitinib citrate) for adults with moderate to severe rheumatoid arthritis (RA) who are not getting adequate treatment from methotrexate. When taken twice daily, Xeljanz works by inhibiting the Janus kinases that are responsible for joint inflammation seen in RA patients. Xeljanz may be used as monotherapy or in combination with other forms of methotrexate or with other nonbiologic disease-modifying antirheumatic drugs (DMARDs).
Over time, about 70% of RA patients stop responding to methotrexate. The safety and efficacy of Xeljanz to treat RA were demonstrated in seven clinical trials—two dose-ranging trials and five confirmatory trials. In all trials, patients treated with Xeljanz experienced improvement in clinical response and functioning, compared with patients treated with placebo. In study subjects aged 65 years and older who were treated with Xeljanz, the frequency of serious infection was higher than in adults younger than 65 years.
The most common side effects of Xeljanz include upper respiratory tract infections, headache, diarrhea, and inflammation of the nasal passages and the upper part of the pharynx. Xeljanz should not be prescribed during an active infection or with any biologic DMARDs and potent immunosuppressants. More information about Xeljanz is available at www.xeljanz.com.
FDA Expands Use of Xarelto to Treat Deep Venous Thrombosis
On November 2, 2012, the FDA expanded the use of Xarelto (rivaroxaban) to include treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as to reduce the risk of recurrent DVT and PE following initial treatment. Xarelto was approved by the FDA in July 2011 to reduce the risk of DVT and PE following hip and/or knee replacement surgery. Later that year, Xarelto was approved to reduce the risk of stroke in patients with nonvalvular atrial fibrillation. The new indication for Xarelto was approved under the FDA’s priority review program, which provides an expedited 6-month review for drugs that offer major advances in treatment or that provide treatment when no adequate therapy exists.
In the EINSTEIN clinical trial program, three phase 3 clinical trials (N=9477) were conducted to ensure the safety and efficacy of the new indication over 3-, 6-, and 12-month follow-up periods. The principal safety outcomes were a composite of major bleeding and clinically relevant nonmajor bleeding. The results showed that Xarelto was as effective as the standard of care (enoxaparin with warfarin followed by warfarin) for treating DVT and PE. Approximately 2.1% of patients treated with Xarelto experienced a recurrent DVT or PE compared with 1.8% to 3% of patients treated with standard care. Discontinuing Xarelto can lead to a higher risk of stroke and thrombotic events. For more information, visit www.xarelto-us.com.
Medical News
Sleep Disruption May Lead to Alzheimer’s Disease in Elders
At the Neuroscience 2012 Convention in October, research was presented indicating a strong link between sleep deprivation and memory loss. A set of cortical brain regions referred to as the default mode network (DMN) shows coherent activity during rest. It has been suggested that decreases in DMN connectivity may be a biomarker of Alzheimer’s disease. While researchers agree that more extensive studies need to be done to fully determine the extent of this correlation, the results of a study by Andrew Ward and colleagues, Massachusetts General Hospital, indicate that older adults (>65 years) with poor sleep habits, such as sleeping fewer hours and waking up frequently during the night, may be predisposed to developing symptoms of Alzheimer’s disease as they continue to age.
The study involved 84 cognitively intact elderly adults (age range, 66-87 years) who were administered the Epworth Sleepiness Scale questionnaire and underwent a resting state functional magnetic resonance imaging scan (fcMRI). The results of the questionnaire, which measured self-reported chronic daytime sleepiness in these patients were related to decreased DMN coherence on the resting state fcMRI. The authors also observed a trend between neuropsychological speed and sleepiness, concluding that, “These findings may have important implications for elucidating age-related and Alzheimer’s disease–related alterations in sleep and network dysfunction.”
Weight Shifting Another Predictor of Falls in Older Persons
Incorrect shifting of body weight is a leading cause of falls among elderly persons residing in long-term care (LTC) settings, according to a new study by Stephen Robinovitch, PhD, and colleagues, published in The Lancet (published online ahead of print October 17, 2012). The researchers noted that a key issue in understanding and preventing falls in LTC facilities is that most of these accidents are not witnessed; thus, in their Canada-based observational study, Robinovitch and colleagues placed cameras throughout hallways and common areas of two LTC facilities to monitor resident falls. None of these cameras were located in bedrooms or bathrooms to respect residents’ privacy. Yet, even with the limited camera views, a total of 227 falls by 130 patients (mean age, 78 years) were captured on video.
Of the total number of falls, 41% were attributed to incorrect weight shifting. Falling by trip or stumble was the next most frequent cause (21%), followed by hit or bump (11%), loss of support (11%), collapse (11%), and slipping (3%). Compared to similar studies in LTC settings, the researchers noted that there was a higher occurrence of falls during standing and transferring of weight, and a lower occurrence of falling during walking. There was also a larger proportion of falls attributed to perturbations in residents’ center-of-gravity than those attributed to base-of-support perturbations. The authors concluded, “By providing insight into the sequences of events that most commonly lead to falls, our results should lead to more valid and effective approaches to balance assessment and fall prevention in long-term care.”
Brilinta Safe and Effective for Acute Coronary Syndrome in Elderly and Younger Patients
In July 2011, the FDA approved
Brilinta (ticagrelor) to improve cardiac outcomes in patients with acute coronary syndrome (ACS). Approval of the blood-thinning agent was largely based on data from PLATO (Platelet Inhibition and Patient Outcomes), a multicenter, double-blind, randomized trial (N=18,622) that compared the efficacy of ticagrelor versus clopidogrel in preventing cardiovascular events in patients with ACS with or without ST-segment elevation. It is known that elderly patients with ACS have a high prevalence of cardiovascular risk factors and an increased risk of recurrent ischemic events and death. It has also been reported that elders are at increased risk of bleeding compared with younger patients on antiplatelet and anticoagulant therapies. However, the clinical benefit and safety of ticagrelor compared with clopidogrel in patients with ACS were not significantly different for patients aged 75 years and older, according to a recent subanalysis of PLATO cohort data conducted by Steen Husted, MD, Aarhus University Hospital, Denmark, and colleagues (Circ Cardiovasc Qual Outcomes. 2012;5[5]:680-688). In their analysis comparing adults aged 75 years and older (n=2878) versus younger adults (<75 years) in the PLATO trial, the researchers found that ticagrelor compared with clopidogrel reduced ischemic outcomes and mortality without increasing overall major bleeding rates in the older group. Additionally, the authors noted that the absolute reduction in all-cause mortality in patients taking ticagrelor was greater in the older patient group (2.6%) than in the younger patient group (1.8%). “The present findings are consistent with the overall results of the PLATO trial, and suggest that the antithrombotic benefits of ticagrelor also apply to the age group >75 years,” Husted and colleagues concluded.
Pancrelipase for Treating Pancreatic Exocrine Insufficiency
In April 2009, the FDA approved Creon (pancrelipase delayed-release capsules) for the treatment of pancreatic exocrine insufficiency (PEI) in patients with cystic fibrosis, chronic pancreatitis, and other conditions. Malnutrition, weight loss, and steatorrhea often result from PEI and increase the risk of morbidity and mortality, especially in older adults. To improve clinical symptoms of PEI, nutritional interventions, including low-fat diets and pancreatic enzyme replacement therapy (PERT), are introduced. Because it significantly improves the coefficients of fat and nitrogen absorption as well as clinical symptoms, PERT with pancrelipase is becoming standard therapy for PEI, according to a recent literature review by Kei Nakajima and colleagues, Josai University, Japan (Core Evid. 2012;7:77-91).
Many double-blind, placebo-controlled trials have been conducted for PERT with pancrelipase in treatment of PEI. Each has shown varying degrees of improvement in steatorrhea and malnutrition and low risk of adverse events, which include tolerable gastrointestinal tract symptoms, headaches and dizziness, and, in rare cases, hyperuricemia (gout) in patients taking pancrelipase for cystic fibrosis.
However, few clinical trials of PERT with pancrelipase have addressed its safety and efficacy in the treatment of pancreatic diabetes, a clinical aspect of chronic pancreatitis and cystic fibrosis that may account for up to 9% of all diabetes cases. It is well known that pancreatic disease can cause endocrine dysfunction, but the etiology of pancreatic diabetes is not as well understood as type 1 and type 2 diabetes. Nakajima and colleagues explained that since patients with pancreatic diabetes are often not obese or they are lean with malnutrition, the condition may be misdiagnosed and thus, inappropriately treated. If pancreatic diabetes is treated with insulin injection, sudden hypoglycemia may result due to insufficient glucagon secretion and the absence of peripheral insulin resistance. The authors suggest that PERT with pancrelipase may be a viable alternative therapy, as it has been associated with increases in fat, protein, and carbohydrate absorption. Increased glucose absorption may reduce the risk of hypoglycemia, enabling more aggressive treatment of hyperglycemia with oral medications and insulin, Nakajima and colleagues wrote. “In terms of the pancreatic exocrine–endocrine relationship, clinicians need to become more aware of the risk of pancreatic diabetes,” they concluded. “Further studies are needed to explore the clinical relevance and appropriate treatment of this disorder.”
Adalimumab Demonstrates Efficacy in Patients With Peripheral Spondyloarthritis
Spondyloarthritis (SpA) is an umbrella term for a family of inflammatory rheumatic diseases that cause arthritis. Forms of SpA include ankylosing spondylitis (AS), peripheral spondyloarthritis, psoriatic arthritis (PsA), and others. Many patients may receive a diagnosis of undifferentiated or unclassified spondyloarthropathy if certain symptoms are present but are not enough to fulfill criteria of a more specific diagnosis; thus, clinicians may be challenged when deciding upon the optimal treatment approach. Among several pharmacological agents used to treat symptoms of SpA, tumor necrosis factor (TNF) blockers are in a newer class of drugs known as biologics. Adalimumab, a TNF-blocker that is injected subcutaneously, is approved by the FDA to treat PsA and AS but is not approved in the treatment of all forms of SpA. In a new study, Jacqueline E. Paramarta and colleagues, Division of Clinical Rheumatology, University of Amsterdam, Netherlands, set out to evaluate the efficacy and safety of adalimumab in patients with SpA not fulfilling diagnostic criteria for AS or PsA (published online ahead of print November 8, 2012. Ann Rheum Dis).
In a randomized, double-blind, placebo-controlled trial, the researchers enrolled 40 patients with active peripheral SpA, diagnosed according to the European Spondyloarthropathy Study Group or Amor criteria, but who did not meet classification criteria for AS or PsA. Patients were treated 1:1 with adalimumab or placebo for 12 weeks, followed by an open-label extension up to week 24. Every 6 weeks, safety and efficacy measurements were performed, with the patient’s global assessment of disease activity at week 12 serving as the primary end point.
At week 12, Paramarta and colleagues observed significant improvement in patients’ and physicians’ global assessment of disease activity, swollen joint count, erythrocyte sedimentation rate, and scores on the Bath Ankylosing Spondylitis Disease Activity Index, and Ankylosing Spondylitis Disease Activity Score (ASDAS). Similar improvement in the adalimumab group was observed in weeks 12 to 24, and clinical response was maintained and, in some cases, augmented at week 24 compared with the placebo group. Moreover, 42% of patients in the adalimumab group compared with 0% to 5% of patients in the placebo group achieved the criteria of “inactive disease” as defined by the ASDAS at week 12 (P=.001 and P=.008, respectively). No significant differences between both groups were noted in the number of adverse effects. “Adalimumab appears to be effective and well tolerated in SpA patients with peripheral arthritis, also in those patients not fulfilling the AS or PsA criteria,” the authors concluded. “Therefore, this treatment should be considered and made available for these patients when their peripheral SpA is refractory to conventional treatments.”
LTC Policy News
Medicare Improvement Standard Challenged
On November 20, 2012, a settlement agreement received preliminary approval in the landmark federal class action lawsuit of Jimmo vs Sebelius that, if permanently approved, would relax the requirements for Medicare beneficiaries seeking coverage of skilled nursing and long-term care services. Filed in January 2011, the suit challenges an interpretation of the Improvement Standard that has allowed Medicare to refuse coverage for patients with progressive or chronic diseases, such as Parkinson’s, Alzheimer’s, and stroke, if they do not show demonstrable improvement in their conditions. The case plaintiffs are seeking prohibition of the continued application of the Improvement Standard and a review to determine whether prior denial of coverage based on the standard should be revised. Under the agreement, Medicare would pay for services that are needed “to maintain the patient’s current condition or prevent or slow further deterioration.”
Among the major provisions of the proposed settlement, a nationwide class would be certified consisting of all beneficiaries who received an adverse administrative decision based on the Improvement Standard that became final and non-appealable on or after January 18, 2011. Many of those class members would be entitled to a re-review of their claims. Additionally, the Centers for Medicare & Medicaid Services (CMS) would be required to revise relevant portions of the Medicare Benefit Policy Manual to eliminate any suggestion that a beneficiary must show a potential for improvement, with the need for skilled care being the determinative factor. CMS also has the option of issuing a ruling on the corrected policy. If the settlement is approved, CMS will have 1 year to carry out an educational campaign informing beneficiaries of the change, at the end of which there would be a 2- or 3-year monitoring period to ensure compliance and class members would have the opportunity for re-review of claims. A Fairness Hearing on the proposed settlement is scheduled for January 2013. To stay up to date with this landmark lawsuit, visit www.medicareadvocacy.org/2012/11/01/jimmo-v-sebelius.
Technology Spotlight
Physicians Can Now Monitor Stroke Patients From Afar With TeleStroke
As part of the trend to modernize patient care by using robotics, video conferencing systems, and other technologies, researchers are working toward finding more efficient ways to provide care to stroke patients and bolster resources to understaffed hospitals. According to the Centers for Disease Control and Prevention, an estimated 800,000 Americans experience a stroke every year, and about 130,000 of those cases are fatal. After a patient has an acute stroke, the most critical time for treatment is within 3 to 4 hours, however, prompt evaluation and treatment may be challenging for patients living in rural areas, where hospital emergency rooms may not have the necessary equipment or neurological expertise to treat stroke patients. Bart Demaerschalk, MD, and colleagues at the Mayo Hospital, Phoenix, AZ, have developed an innovate new telemonitoring system called TeleStroke that enables physicians to remotely view patient’s files and vital signs, take and examine radiographs and computed tomography scans, and recommend treatment options to the hospital staff. The TeleStroke system facilitates communication between the physician and the remote hospital staff with a robot that has digital video cameras and an Internet connection. The Mayo Clinic in Arizona has been working with stroke telemedicine since 2007. Their program has since grown to 11 remote sites. To subscribe to the Mayo Clinic’s stroke telemedicine service at your clinic, visit www.mayoclinic.org/stroke-telemedicine.
Product Spotlight
Managing Fecal Incontinence With a Tissue-Bulking Gel
As patients age, the probability of fecal incontinence increases greatly. Almost 50% of the elders residing in nursing homes experience bouts of fecal incontinence. Some elders are unlikely to report fecal incontinence to their healthcare providers due to embarrassment or believing that it is a normal part of aging. However, the condition can make it difficult to perform activities of daily living and may be indicative of a serious underlying condition, such as poor diet, diarrhea, constipation, or damage to the rectum or rectal walls. Dietary changes and antimotility medications are used to treat the condition, but once these fail, patients may have another treatment option: Solesta, a biocompatible tissue-bulking gel that is injected into the layer of tissue underneath the anus. Approved by the FDA on May 27, 2011 to treat fecal incontinence, the
sterile gel is made of dextranomer and sodium hyaluronate, both naturally made materials. Treatment with Solesta requires a series of four shots to narrow the opening of the anus in an effort to reduce uncontrolled bowel movements.
Solesta was clinically tested in approximately 200 patients across the United States and Europe. Patients were randomly selected to receive either Solesta or a placebo over a period of 6 months. Just over 50% of the patients receiving Solesta saw an improvement in the number of incontinence episodes, compared with about 30% of the patients receiving the placebo. Those on Solesta had a smaller risk of abdominal pain, constipation, diarrhea, and fever. Based on this trial, it was recognized that Solesta can provide symptom relief to some patients, but it is not a cure.
Possible side effects of Solesta include pain or discomfort in the rectum/anus, possible light rectal bleeding after the procedure, and a rare risk of infection or inflammation around the anus. Solesta is contraindicated in persons who have received radiation treatment in the pelvic area, have rectal or anal problems (such as tumors), have an active inflammation of the bowels, have trouble fighting off infections, or have had a device/material already placed in their rectum or anus. For more information about Solesta, visit www.solestainfo.com.
Integrated Wall System Saves Time and Space in Clinical Care Settings
Efficiency and accuracy are key qualities of patient care and clinical decision-making. When time with patients is lost searching for pieces of equipment, untangling cumbersome cords, and digging through files for patient data, it is time to upgrade your system. The Connex Integrated Wall System by Welch Allyn organizes the tools needed for physical assessment and vitals management into one central location. With this all-in-one system, patient data is collected quickly and accurately, allowing the physician to immediately view results and send them directly to an electronic medical records system, reducing the risk of recording errors via manual transcription. The wall system saves valuable floor space and includes a large graphic display touchscreen and four USB ports for users to customize and expand the system features as the need arises. Its features include integrated otoscope and opthalmoscope, ear thermometry, pulse oximetry, blood pressure test, and programmable visual and audible alarms. For a complete list of features and purchasing information for the Connex Integrated Wall System, visit www.welchallyn.com/promotions/connex-evd/connex-iws.
Ask the Expert
Tetrabenazine in the Treatment of Movement Disorders
Nationwide, an estimated 30,000 individuals have Huntington’s chorea, an incurable neurodegenerative disease. There is no known way to stop progression of the disease, thus the goal of treatment is to slow down the symptoms and employ palliative care. In 2008, the FDA approved Xenazine (tetrabenazine), the first medication to treat patients with chorea associated with Huntington’s disease. There has been much research evaluating the efficacy of tetrabenazine in the treatment of other movement disorders as well. Jack Chen, PharmD, and colleagues at the Movement Disorders Clinic, Loma Linda University, Loma Linda, CA, recently published a comprehensive review of the literature on tetrabenazine (Clin Ther. 2012;34[7]:1487-1504.). Annals of Long-Term Care® (ALTC) had the opportunity to interview Dr. Chen about the risks and benefits of tetrabenazine in the treatment of Huntington’s chorea and other movement disorders.
ALTC: You recently reviewed the medical literature on tetrabenazine. Can you briefly summarize your findings?
Dr. Chen: Tetrabenazine was FDA-approved based on efficacy and safety data for chorea associated with Huntington’s disease, but tetrabenazine is also useful for a variety of other hyperkinetic movement disorders that are also considered “rare” or “orphan” diseases. Examples include tardive dyskinesia, dystonias, and tic disorders. The symptoms and functional outcomes of these movement disorders can be very distressing to patients and a challenge for clinicians to treat. My coauthors and I wrote the article to help clinicians better understand the role and use of tetrabenazine, not only in Huntington’s chorea, but also in these other movement disorders.
Tetrabenazine has been used worldwide for decades, but it was only approved in the United States as a treatment for Huntington’s chorea in August 2008. Why do you think it took so long for the FDA to approve it?
Prior to FDA approval, physicians were able to prescribe tetrabenazine and patients were able to purchase and import the drug from other countries provided they had a prescription for an approved Investigational New Drug. For example, the Movement Disorders program at Baylor College of Medicine accumulated and published much of the outcomes data for tetrabenazine in various hyperkinetic movement disorders.
Basically, there are many conditions (eg, Huntington’s disease, Tourette syndrome), which affect such small numbers of individuals residing in the United States that these conditions are considered rare here, and adequate drugs for many of these conditions have not been developed. Drugs for these conditions are commonly referred to as “orphan drugs.” Since so few individuals are affected by any one rare condition, a pharmaceutical company that develops an orphan drug may reasonably expect the drug to generate relatively small sales in comparison to the cost of developing the drug and consequently to incur a financial loss. With the Congressional passage in 1983 of the Orphan Drug Act, changes in federal laws provided incentives for pharmaceutical companies to develop promising orphan drugs. Tetrabenazine is an example of an orphan drug that was FDA-approved as a result of the Orphan Drug Act.
Can you briefly explain tetrabenazine’s mechanism of action?
The primary pharmacological action of tetrabenazine is to inhibit the human vesicular monoamine transporter 2 (VMAT2). Inhibition of VMAT2 prevents translocation of neurotransmitter monoamines (eg, dopamine, norepinephrine, serotonin) from the cytoplasm into synaptic vesicles; therefore, the monoamines are exposed to premature degradation and cannot be stored for synaptic release. Pharmacological reduction of monoamines in brain regions, such as the striatum, is believed to contribute to attenuation of hyperkinetic movements. The drug also has metabolites that possess similar pharmacologic activity.
Tetrabenazine can be used for multiple movement disorders; in your review of the literature, did you find that one disorder responded better to tetrabenazine than others?
Tetrabenazine should be considered a first agent to treat chorea of Huntington’s disease.
Are there any major side effects in patients using tetrabenazine? If so, were they common among all patients or specific to age, sex, or dosage?
Common side effects include somnolence, depression, and Parkinsonism. These side effects are dose-related and can be managed by dose reduction. Elderly patients may be at greater risk for experiencing tetrabenazine-induced Parkinsonism, and patients with a history of depression are at greater risk of tetrabenazine-induced depression.
How do outcomes and quality of life of patients taking tetrabenazine compare with those of patients who do not take treatment for their involuntary movement disorders?
Tetrabenazine can improve functional outcomes, particularly for those with severe involuntary movements, and with improvement of functional outcomes, quality of life is also improved. Many of these involuntary movements can also be stigmatizing to patients, and improvement of symptoms can enhance personal and social well-being.
