First Report® American Society of Health-System Pharmacists Midyear Clinical Meeting
Orlando, FL; December 7-11, 2008
Using DMARDs in the Treatment of Rheumatoid Arthritis
Orlando, Florida—In 2008, the American College of Rheumatology developed recommendations for treating rheumatoid arthritis (RA) with biologic and nonbiologic disease-modifying anti-rheumatic drugs (DMARDs). Jeffrey Curtis, MD, MPH, Associate Director, University of Alabama at Birmingham Center for Education and Research on Therapeutics, and Director of the Arthritis Clinical Intervention Program, presented those treatment recommendations at the ASHP meeting.
Dr. Curtis began his presentation by stating that the recommendations are “advisory, not prescriptive,” and the ultimate goal of the multidisciplinary task force panel was to improve healthcare to ensure that physicians are providing high-quality, appropriate, and cost-effective care to their patients. The panel was charged with constructing evidence-based recommendations covering five domains: (1) therapeutic indications for use of the agents; (2) assessing the clinical response; (3) monitoring of side effects; (4) appropriate ways to screen for tuberculosis (biologics only); and (5) issues related to cost and patient preference (biologics only).
The RA therapies included in the recommendations were divided into nonbiologics and biologics. The nonbiologics included hydroxychloroquine (HCQ), leflunomide (LEF), methotrexate (MTX), minocycline (MIN), and sulfasalazine (SSZ). The biologics included anti-tumor necrosis factors (anti-TNF) (etanercept, infliximab, and adalimumab), abatacept, and rituximab.
The panel initially addressed the need to evaluate the duration of the disease, the activity level of the disease, and the prognosis in order to make recommendations for therapeutic indications. Dr. Curtis gave examples of instruments that clinicians could use to assess disease activity, including the Health Assessment Questionnaire Disability Index, the Disease Activity Score 28, the simplified disease activity index, the clinical disease activity index, the rheumatoid arthritis disease activity index, the patient activity scale, and routine assessment of patient index data. He said that the time of collection required for these tools ranges from approximately 30 seconds to 5 or 10 minutes.
He also outlined examples of features of a poor prognosis for RA, including functional limitation defined by using a standard scale, extra-articular disease (rheumatoid nodules, Felty’s syndrome, or RA lung disease), positive rheumatoid factor, positive anticyclic citrullinated peptide, or bony erosions by radiograph. Disease duration was grouped “somewhat arbitrarily,” according to Dr. Curtis, into three treatment pathways: (1) those whose disease was less than 6 months duration; (2) those with 6-24 months duration of disease; and (3) those with more than 24 months duration of disease. An additional group of patients with very severe disease but who were DMARD-naïve and newly initiated to therapy were considered separately. Dr. Curtis said that those patients had “tremendous cost implications for payers, health systems, pharmacists, clinicians, and patients.”
Dr. Curtis then described the algorithms for treatment recommended by the panel. For patients with disease duration of less than 6 months with low disease activity, the panel recommended as initial therapy LEF, MTX, or SSZ as monotherapy for patients with features of poor prognosis. For patients without features of poor prognosis, the panel also recommended HCQ or MIN (or LEF, MTX, or SSZ). For patients with moderate or high disease activity, with features of poor prognosis, the panel also recommended LEF, MTX, or SSZ, but added the use of combination therapy of MTX plus HCQ, MTX plus SSZ, or MTX plus SSZ plus HCQ. For those without features of poor prognosis, the panel recommends a “somewhat less aggressive recommendation with monotherapies of LEF, MTX, SSZ, or MTX plus HCQ combination,” Dr. Curtis said.
For patients with disease duration of 6-24 months, low disease activity, and no features of poor prognosis, the panel recommended the use of LEF, MTX, SSZ, or HCQ. For patients with features of poor prognosis, the panel added combination therapy of MTX plus SSZ plus HCQ to the recommended monotherapies of LEF, MTX, or SSZ. For patients with moderate or high disease activity and no features of poor prognosis, the panel recommended monotherapy of LEF, MTX, or SSZ, or combination therapies of MTX plus HCQ, MTX plus SSZ, MTX plus LEF, MTX plus SSZ plus HCQ, or SSZ plus HCQ.
For patients with more than 2 years of disease duration, low or moderate disease activity, and no features of poor prognosis, the panel recommended LEF, MTX, SSZ, or a combination therapy of MTX plus HCQ. For those with low or moderate activity and features of poor prognosis, the panel recommended those therapies as well as combination therapies of MTX plus LEF or MTX plus SSZ plus HCQ. For patients with more than 2 years of disease duration, high disease activity, and no features of poor prognosis, the panel recommended monotherapy of SSZ, or LEF, or MTX, as well as the combination therapies of MTX plus HCQ, MTX plus LEF, MTX plus SSZ, or MTX plus SSZ plus HCQ. All but the monotherapy of SSZ were recommended for patients with high disease activity and features of poor prognosis.
Biologic DMARDs carry a separate set of recommendations. Patients are stratified into three groups: (1) those with disease duration of less than 6 months (mostly DMARD-naïve); (2) those with disease duration of more than 6 months who have failed on MTX therapy; and (3) those with more than 6 months of therapy with MTX or after other sequential DMARDs.
The recommendation for patients with RA for less than 6 months duration and low to moderate disease activity is the nonbiologic DMARD algorithm. Patients with high disease activity for less than 3 months and no features of poor prognosis would also be recommended to receive a nonbiologic DMARD. If those patients have features of poor prognosis, but the cost of insurance coverage is limiting, they would be recommended for a nonbiologic medication. If there are no cost limitations, the first-line therapy recommended would be anti-TNF therapy in conjunction with MTX, even for patients with only 3-6 months of disease duration.
Patients with disease duration of less than 6 months who have failed MTX, have low disease activity, and no features of poor prognosis are referred to nonbiologic DMARDs. For those with moderate or high disease activity and features of poor prognosis, anti-TNFs with or without MTX would be recommended.
For patients who have failed on MTX and other nonbiologic DMARDs, those with low disease activity would be referred to the nonbiologic DMARDs algorithms. Those with moderate to high disease activity and no features of poor prognosis would receive nonbiologic DMARDs or anti-TNF therapy. Those with features of poor prognosis would receive anti-TNF therapy or abatacept or rituximab.
Dr. Curtis continued his presentation with contraindications for starting or resuming nonbiologic DMARDs and biologic DMARDs. He also discussed the recommendations for monitoring for tuberculosis for patients receiving biologic therapies, safety monitoring, risk surveillance, and preventive immunizations recommended by the task force panel.
He concluded by outlining the future of the recommendations, including the challenges of dissemination and implementation, and some of the limitations of the recommendations, such as the lack of attention to NSAIDs, glucocorticoids, or less common biologic DMARDs, and the need for the recommendations to be revised periodically to avoid becoming outdated.
Clinic Seeks Link Between Cognitive Impairment and Successful Anticoagulation
Orlando, Florida—Pharmacists can assist in identifying and assisting elderly patients with cognitive impairment who are receiving anticoagulation therapy, according to Travis E. Sonnett, PharmD, Clinical Assistant Professor, Washington State University, who spoke at an educational session during the ASHP meeting. He discussed the prevalence of dementia, identified screening tools for cognitive impairment, discussed the impact of early detection and treatment initiation, and reviewed treatment options and their profiles.
Dr. Sonnett presented estimates on the prevalence of Alzheimer’s disease (AD) from the National Institutes of Health. According to estimates, about 5% (~ 4.5 million) of Americans age 65 to 74 have AD. The prevalence among Americans older than 85 is about 50%, and the number of individuals with AD is expected to triple with the next generation of Americans. He said the adjusted prevalence of AD or other dementia is 25% among elderly hospital patients, 47% among nursing home patients, and 50% among elderly residents of assisted living facilities. Also, 24% of patients receiving home health services from Medicare or Medicaid have AD or related dementia.
“We know that detection and diagnosis of Alzheimer’s disease and related dementia is grossly underestimated,” Dr. Sonnett said, adding that the highest estimates suggest that about 40% of patients with an AD or dementia diagnosis actually get diagnosed. “That means that 6 out of 10 patients with an AD or related dementia are out there in the community undiagnosed.”
The cost of providing healthcare to Medicare beneficiaries with AD triples, on average, Dr. Sonnett said. For the year 2000 it was reported that the cost of treating a patient with heart disease and AD was $21,538 compared with $11,078 for patients with heart disease alone. Hospital costs were $12,273 for patients with heart disease and AD compared with $6559 for patients with only heart disease.
Emphasizing the importance of early diagnosis and treatment, Dr. Sonnett said that rather than looking for dementia in the early stages of suspected AD, physicians and pharmacists can look for mild cognitive impairment such as a memory complaint or abnormal memory loss for a patient’s age, but should be mindful of potential temporary memory loss from medications. By identifying AD early, patients have increased opportunities to make maximum use of available treatments and services, and successful therapy with a cholinesterase inhibitor can ease caregiver burden by helping patients with AD improve, maintain, or slow cognitive and functional decline.
Atrial fibrillation, he said, is an indicator for anticoagulation therapy and in addition to producing a five times greater stroke risk, it is associated with increased risk of cognitive decline and reduced hippocampal volume. This, in turn, can lead to impairment of learning, memory, and executive function.
Pharmacists, Dr. Sonnett said, can help patients with cognitive impairment receive optimal anticoagulation therapy with drugs such as warfarin. He went on to describe a study conducted at a Spokane, WA, anticoagulation clinic in which the Mini-Cog dementia screening tool was used as part of a health-improvement initiative to improve care quality. They performed a basic analysis to find relationships between the number of visits patients made to the clinic, the number of dosage changes, international normalized ratio (INR) values based on each visit, and overall success in achieving anticoagulation goals.
In the study, patients ≥ 60 newly admitted for treatment received a Mini-Cog assessment as part of their initial admission process. Previously admitted patients received a Mini-Cog as well, with follow-up every 6 months. They reviewed patient risk factors and cognitive impairment to identify correlations with the quality of their anticoagulation therapy. The study included 300 patients (38% male) whose average age was 76. The failure rate on Mini-Cog exams was 20%, with an average failure age of 77. INR readings found to be out of target range were recorded for 44% of subjects, and 42% had a dosage change.
The study showed that the population of cognitively impaired patients was higher than in national studies. “What we did not find was a correlation between receiving anticoagulation therapy and being out of target range more so if you failed the cognitive function test,” Dr. Sonnett said.
He said typical success rate of remaining in target range for patients who did not fail the Mini-Cog was 65% versus 56% for the population that did fail. “There is a difference, just not as great as we expected,” Dr. Sonnett said.
Sixty patients in the study were identified as cognitively impaired without a current dementia diagnosis. This, Dr. Sonnett said, means that patients who are cognitively impaired or test as cognitively impaired have about a 33% risk of developing some form of dementia over the next 3 years. Five patients were referred for neurological follow-up, and all referred for follow-up were diagnosed with a form of AD or related dementia and initiated on treatment.
“While this is not a statistically significant outcome, from the clinical standpoint this is outstanding,” he said. “Even getting 1 patient a referral and identified would have been a success in that aspect.”
Management of Hip Fracture Risks Needed for Elderly Patients
Orlando, Florida—Experiencing a hip fracture is a common concern among geriatric patients because of the increased risk of mortality, reduced quality of life, and loss of independence that can follow. At an educational session during the ASHP meeting, three presenters discussed treatment options for patients who have had hip fractures, osteoporosis, and osteoarthritis but emphasized the importance of preventive measures to help seniors avoid these medical conditions in the first place. The presenters discussed complications associated with hip surgeries, chronic conditions associated with hip fracture, and treatments for osteoarthritis.
The first presenter was Sheila Wilhelm, PharmD, BCPS, Clinical Assistant Professor at Wayne State University, Detroit, MI. Dr. Wilhelm used a case study of a patient diagnosed with a low-trauma hip fracture requiring hip arthroplasty in her discussion, which was intended to describe normal hip anatomy, common types of hip fracture, and surgical options for hip fracture repair. She told the audience that in 2004 hip fractures were responsible for 320,000 hospital admissions, 75% of which occurred in women. Among seniors, more than 90% of hip fractures are due to falls. Risk factors include advancing age, low bone density and osteoporosis, prior or family history, inactivity, and tobacco use.
Patients who experience a hip fracture have a 40% likelihood of not regaining their pre-fracture walking ability, and half will not regain their full ability to perform the activities of daily living. They also have a 20-25% mortality risk within a year of the fracture, and about 25% will remain in a nursing facility for a year or more, even if they were previously independent. Surgical options include total hip arthroplasty (THA) or hip fracture surgery (HFS) such as hip resurfacing, hemiarthroplasty, and open reduction internal fixation (ORIF).
Although there are several complications that can arise after surgery, the presentation focused on preventing venous thromboembolism (VTE). Subtopics were VTE pathogenesis, preventive anticoagulants, patient-specific planning, and resolution of medication issues related to preventing coagulation after a hip fracture. Dr. Wilhelm said that vascular damage can arise as a direct result of trauma from hip surgery or due to the advancing age of the patient. She said that in clinical trials in which patients underwent hip or knee arthroplasty, HFS, major trauma, or spinal cord injury with no VTE prophylaxis and mandatory venography, VTE was found in 40-80% of patients.
Pharmacologic agents highly recommended for VTE prophylaxis are low-molecular-weight heparin, fondaparinux, and warfarin. Low-dose unfractionated heparin is not recommended for persons who have had THA, but is recommended after HFS; mechanical prophylaxis is recommended for both THA and HFS, but only in patients at high risk for bleeding. Aspirin is not recommended as a stand-alone pharmacologic measure to prevent VTE.
Dr. Wilhelm told the audience that although the average length of stay for THA is 5-6 days, coagulation activity can continue for at least 4 weeks, and the risk for VTE can last 3 months. The current recommendation is to provide extended prophylaxis after THA or HFS for at least 10 days and up to 35 days after surgery, and Dr. Wilhelm presented data showing that VTE prophylaxis is underutilized. Finally, she said that pharmacist involvement can increase VTE prevention utilization and patient and family education.
The second segment of the discussion was led by Mary Beth O’Connell, PharmD, BCPS, FASHP, FCCP, Associate Professor, Wayne State University, who discussed chronic conditions associated with hip fracture, beginning with osteoporosis. “Even though [osteoporosis] is a public health concern, most of our seniors are not getting adequate education or diagnosis,” she said before presenting data showing that the incidence of osteoporotic fractures among U.S. women is about four times greater than the risk of myocardial infarction, stroke, or breast cancer.
New guidelines for the prevention and treatment of osteoporosis were published this year by the National Osteoporosis Foundation (NOF) and are available free of charge. The new guidelines focus on both women and men. These guidelines include new criteria for a central bone density test (DXA). World Health Organization (WHO) criteria are still the standard for determining a diagnosis, Dr. O’Connell said. A new tool available online is the FRAX WHO Fracture Risk Assessment Tool. This predicts the likelihood of a major hip fracture as well as the risk of hip fracture within the next 10 years.
FRAX evaluation requires information such as patient age, body mass index, fracture history, parental hip fracture in the patient’s mother or father, and current smoking status. Other factors included in the evaluation include use of glucocorticoids, rheumatoid arthritis, bone mineral density, and alcohol use. Dr O’Connell said that alcohol use is assessed primarily because it increases the risk of falls, but in patients who consume more than 3 units per day, alcohol use becomes an independent risk factor.
The new NOF guidelines for drug treatment have expanded the indications for treatment, she said, mainly to utilize information gleaned from use of the FRAX tool. Treatment guidelines still include lifestyle modification such as increasing physical activity and weight-bearing exercise, smoking cessation and avoidance, and proper nutrition. A major change, she said, is vitamin D intake. Previously, 400 units of vitamin D were recommended for adults and 600 units for seniors. This has been changed to a minimum of 800-1000 units. Prevention of falls is also an area of emphasis. Drug therapies for osteoporosis prevention include bisphosphonates to prevent resorption of calcium from the bones as well as raloxifene, calcitonin, and teriparatide.
Dr. O’Connell concluded that all seniors should adopt a bone-healthy lifestyle and undergo DXA tests and FRAX evaluation. Those with osteoporosis should be treated with bisphosphonates, and older persons should receive at least 1200 mg of calcium and 800-1000 units of vitamin D daily. She said that only zoledronic acid has been proven effective for secondary fracture prevention, and it also decreases mortality.
Next, Mary Beth Elliott, PharmD, PhD, Associate Professor, University of Wisconsin-Madison School of Pharmacy, discussed immediate and long-term considerations for the treatment of osteoarthritis in frail older patients. Dr. Elliott provided an overview of osteoarthritis and discussed the efficacy and safety of pharmacologic options, as well as the personalization of patient care plans. She said that osteoarthritis is the most common and costly form of joint disease and affects 16 million people in the United States. Risk factors include age, female gender, obesity, muscle weakness, and sports activities.
Nonpharmacologic therapies for osteoarthritis include patient education and self-management programs, weight loss, exercise, physical and occupational therapy, and range of motion exercises.
Acetaminophen is considered one of the top drugs of choice used to treat osteoarthritis, Dr. Elliott said. She noted the importance of a pharmacist in managing this medication because patients may be taking other drug therapies that contain acetaminophen, leading to the possibility that they may exceed the maximum 4-mg-per-day dosage. Some studies have found that acetaminophen can provide similar efficacy to nonsteroidal anti-inflammatory drugs (NSAIDs), even though patients sometimes prefer NSAIDs, which can be more effective at reducing pain. Patient response can vary.
Dr. Elliott said that there is no decisive evidence that any NSAID is superior for all patients. NSAID toxicities include dyspepsia, gastrointestinal bleeding and ulceration, cardiovascular risk, and renal insufficiency. She added that 16,000 deaths per year in the United States are attributed to NSAID use and that most are from gastrointestinal effects. Proton pump inhibitors are effective in reducing the risk of gastrointestinal bleeding and are recommended by the American College of Cardiology.
A newer option for treating osteoarthritis is diclofenac gel, which Dr. Elliott said is expensive and not appropriate for all patients, but provides significantly lower systemic exposure. Early studies of glucosamine and chondroitin were promising, but later studies have cast doubt on efficacy. Additional agents are capsaicin creams, tramadol, and local injections of corticosteroids and hyaluronic acid.
Dr. Elliott concluded her presentation by stating the importance of proper diagnosis and assessment of pain, function, and patient goals. Education and nondrug therapies should always be the first option, and drug therapy can be tailored for patient preference, effectiveness, and risk factors.