CERTs.About.Annual Reports.Year 4.CERTs Progress.Informing.Providers.Patients

The CERTs are committed to educating and informing health care providers and patients about the results of our research in therapeutics. Understanding the risks and benefits of medical therapies is a critical step to improving the safety and effectiveness of their use. It is also critical to ensure that patients and providers have the knowledge needed to use medical therapies appropriately.

A recent and significant health care issue was the voluntary withdrawal of Vioxx® (rofecoxib) from the market by its manufacturer, Merck & Co. This action was taken in response to indications that the popular drug increased the risk of cardiovascular events (including heart attack and stroke).

Rofecoxib is a cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drug (NSAId) prescribed for the treatment of arthritis and a variety of musculoskeletal conditions. COX-2 drugs were developed as alternatives for patients needing chronic treatment for pain or inflammation who were at increased risk of gastrointestinal side effects of NSAIDs.

A CERTs study examined rofecoxib use and found that it was frequently prescribed and used at higher than recommended doses. Rofecoxib was approved for chronic treatment of osteoarthritis at doses of 12.5 mg and 25 mg, and for acute pain at doses of 50 mg for up to 5 days. However, in examining prescriptions for rofecoxib among people aged 50 or older enrolled in TennCare, researchers found that the use of high doses (50 mg) of rofecoxib for longer than 5 days was relatively common. This suggests that physicians were prescribing doses approved for acute pain and chronic arthritis interchangeably, despite emerging data and warnings that some COX-2 drugs cause serious cardiac side effects.

Another medication with potentially serious risk is dofetilide (Tikosyn®), an oral anti-arrhythmic medicine for patients with atrial fibrillation and atrial flutter. Because the medication has been associated with torsades de pointes, a potentially fatal irregular heart rhythm, the manufacturer developed a distribution and management program to minimize the risks.

The CERTs conducted a study to see whether the risk management program was effective in improving compliance with dosing and monitoring recommendations. Researchers examined data for patients receiving either dofetilide or sotalol (another drug to treat arrhythmia) in the 12 months after dofetilide became available. Sotalol, like dofetilide, is used to treat atrial fibrillation and flutter and also carries a risk of torsades de pointes. Sotalol already had been on the market for treatment of ventricular arrhythmias before its approval for atrial fibrillation/flutter, and at the time of the study, no risk management program for its use for atrial fibrillation/flutter was in place.

Comparing the prescribing of dofetilide (with a risk management program) and sotalol (without a risk management program), the researchers found that the starting dose of dofetilide was more often correctly adjusted on the basis of renal function than was the starting dose of sotalol. In addition, baseline and follow-up chemistries and ECGs were more frequently acquired as recommended in patients receiving dofetilide than in those receiving sotalol. This suggests that the dofetilide risk management program was effective in getting prescribers to adhere to dosing and monitoring recommendations on the label.

Yet the study uncovered what may be an unanticipated effect of the risk management program. Dofetilide was used markedly less often than sotalol. This suggests that physicians' avoidance of prescribing drugs with demanding risk management programs may undermine the purpose of such programs.

In another project, the CERTs evaluated the impact of several Federal and industry communication efforts on the risk of tuberculosis infections in rheumatoid arthritis patients using biological therapies. Following its licensure, potential adverse side effects of infliximab (Remicade®) were reported, including tuberculosis. The product prescribing information was changed to recommend a tuberculin skin test before patients received the drug. This was also reinforced by several risk communication efforts.

In the CERTs study, patients who had used infliximab were identified from 11 health plans located throughout the United States, and physician claims data were examined to determine whether the patients had received a tuberculin skin test. Over the 30-month time period, the overall tuberculin skin testing rate doubled from 15.4 to 30.9 percent, and the rate of pre-infliximab treatment testing increased from zero to 27.7 percent. Tuberculin skin testing rates were significantly higher in female patients, for those with a diagnosis of rheumatoid or psoriatic arthritis, and for those whose prescribing physician was a rheumatologist.

Although the tuberculin skin testing rate was less than favorable overall, tuberculin skin testing doubled over 30 months of ongoing risk communication efforts. (Under-ascertainment of skin testing likely occurred.) This study demonstrated a significant change in patient care following Federal industry risk communication efforts, a finding that has not been consistently seen in other therapeutic areas.

Previous work reported in the Year 4 CERTs Annual Report led to the discovery that methadone can cause a rare cardiac arrhythmia, torsades de pointes, and in some cases, death. Methadone is a life-saving therapy for heroin addiction and is increasingly used to treat pain for cancer patients. It is important to understand the risks associated with developing torsades de pointes while taking methadone in order to offer recommendations to practitioners that will enable this drug to continue to be used safely.

The CERTs established a partnership with DrugLogic, formerly QED Solutions, Incorporated, that enables our researchers to use a computer program to more easily access reports of adverse events associated with methadone reported to the FDA MedWatch program. Examination of these adverse events suggests that dosages that fall within the recommended range for methadone maintenance treatment (60-100 mg per day) were associated with torsades de pointes and/or a prolonged QT interval. Risk factors that have been previously identified with other drugs known to cause torsades de pointes were included in these reports: female gender, interacting medicines, structural heart disease, hypokalemia (low levels of potassium in bloodstream), and hypomagnesemia (low levels of magnesium in bloodstream).

Based on these results, CERTs researchers suggest that practitioners obtain a thorough history to identify risk factors for torsades de pointes.

After initial studies revealed that the risk of a potentially fatal cardiac arrhythmia, torsades de pointes, was not confined to a particular drug class or type, the CERTs developed a list of drugs that prolong the QT interval and/or induce arrhythmias. This information was made available to practitioners and patients on a Web site, www.qtdrugs.org. An e-mail address posted on the site enables the public to ask questions about specific drugs. Over the past 2 years, the lists have been improved and modified to reflect new drugs introduced in the market and the reevaluation of old drugs as new information becomes known. At the time of publication, the drug lists are visited over 2,000 times per month and have been cited in numerous textbooks and in peer-reviewed journals.

COMBINING OVER-THE-COUNTER MEDICATIONS, HERBS, AND SUPPLEMENTS WITH PRESCRIPTION DRUGS

The use of over-the-counter medications, herbs, and supplements in combination with prescription drugs is of growing concern because of adverse drug interactions. The CERTs developed an interactive "virtual medicine cabinet" as a colorful educational tool for health care consumers who visit one of its Web sites: www.azcert.org. The medicine cabinet opens and displays familiar-looking bottles and packages showing generic examples of multiple classes of over-thecounter medications typically found in people's medicine cabinets. Visitors can click on the medicines to find out how safe they are in combination with other drugs and find links to additional information at the National Library of Medicine's Web site, MedlinePlus. gov. Designed specifically to attract and inform busy, non-technical audiences, the virtual medicine cabinet has been visited over 4,000 times since its creation in January 2004.

DISCOVERING THE ROLE OF HERBAL REMEDIES AND SUPPLEMENTS USED BY HISPANIC WOMEN WITH DIABETES

Assessing the use of herbal remedies is an important first step in educating patients about the risk associated with combining prescribed medications, herbal remedies, and supplements. One CERTs study identified different types of herbal remedies and supplements used by a group of Hispanic women receiving treatment at community health centers in Southern Arizona. The current evidence on efficacy, interactions, and adverse effects associated with the use of particular herbs and supplements was also examined. More than 90 percent of the subjects reportedly used one or more herbal remedies, which underscores the need for practitioners to communicate with their patients about the use of herbal remedies and supplements.

The use of medications during pregnancy poses a potential risk to both mother and fetus. Because so little is known about the safety of medicines used during pregnancy, health care databases are important tools for identifying possible harm from prescription drug exposures during pregnancy.

Much of what we know to date has come from studies of women who took certain medications during pregnancy and then agreed to have their progress tracked through delivery. These studies, however, can tell us only about certain drugs, and we need to know about the potential effects of many more drugs previously unstudied. CERTs investigators are addressing this problem by using a health care database, the United Kingdom General Practice Research Database, to develop and validate standard definitions of specific birth defects. Once we have standard definitions, we can make them available for use in other large databases to screen for potential adverse pregnancy outcomes from a larger number of drugs.

To assess how often unborn babies are exposed to drugs that may cause them harm, the investigators recorded drug use before and during pregnancy for 152,531 women in eight different U.S. health systems and geographic regions. Of these women, 71,913, or almost half, were prescribed drugs that fall within categories C, D, and X of the FDA's pregnancy risk classification system. Drugs in category C have unknown risks in human pregnancy but the benefits may outweigh the risks during pregnancy; those in D have evidence of risk in human pregnancy but the benefits of the drug may outweigh the risks of use during pregnancy; those in X have demonstrated risks and/or positive evidence of risks in human pregnancy, such that the risks clearly outweigh any possible benefit of the drug. The study suggests that a signifi- cant number of women become pregnant while taking drugs for which the risks are unknown or demonstrated.

Another CERTs project studied the use of prescription drugs during pregnancy, focusing specifically on drugs in the FDA's category X. The group looked at how many of 95,284 pregnant women in TennCare filled prescriptions for category X medications. Within the group, 391 filled such prescriptions, meaning that about 4 in 1,000 fetuses were exposed to potentially harmful medication. Women over the age of 35 and those enrolled in TennCare because of chronic disabilities were at the greatest risk for filling prescriptions for category X drugs. Study results underscore the need to inform both physicians and women so they can consider the risks in taking these medications during pregnancy.

IDENTIFICATION OF POTENTIALLY INAPPROPRIATE PRESCRIBING PATTERNS FOR CHILDREN AND THE ELDERLY 14, 15, 16

Children are extremely vulnerable to dosing errors. In the United States, children visit a physician an average of 1.8 times each year, and in as many as 60 percent of these appointments, they receive prescriptions for medication. Yet despite data showing that each year children experience serious and even fatal consequences from medication errors, little is known about these problems for children outside hospital settings.

To determine the frequency of dosing errors in the outpatient setting, the CERTs examined records for 1,933 randomly selected children who had been dispensed new prescriptions for commonly prescribed medications. The study found that dosing errors occur frequently in outpatients. Approximately 15 percent of children were dispensed a medication that constituted a potential dosing error, almost evenly divided between potential overdoses (8 percent) and underdoses (7 percent). Analgesics, or drugs for pain relief, were the most likely to be overdosed. This is a matter of concern because analgesics have a higher than average likelihood of serious adverse effects associated with improper dosing. Prescriptions for anti-epileptic drugs were the most likely to be underdosed.

The risk of medication errors is higher for the youngest patients, those least equipped to alert parents or providers to problems. The study found that children under 4 were 50 percent more likely to be prescribed a potential overdose than children ages 4 to 12, with asthma and allergy medications and antibiotics the most likely to be associated with medication errors in this youngest age group. The study underscores the need for more work on the impact of these errors and on effective strategies to prevent them.

Also vulnerable to dosing errors are people 65 years of age and older, who make up less than 15 percent of the U.S. population but account for nearly one-third of prescription drug consumption. The chance of adverse reactions to drugs increases with age, a factor complicated by the fact that many older people take several medications simultaneously.

In order to determine rates of inappropriate medication use, the CERTs examined records for 157,517 patients age 65 and older in a nationally representative managed care population. The study examined the use of 33 potentially inappropriate medications over an 18-month period. The list includes a range of pain killers, antidepressants, and muscle relaxants classi- fied as risky for elderly consumption.

From January 2000 to June 2001, almost 1 in 3 of those surveyed received at least 1 inappropriate medication, with about 5 percent receiving at least 1 of the 11 medications classified by an expert panel as "always avoid." Overall, the use of inappropriate medications was greater among women (32.4 percent) than among men (24.2 percent), a gender difference consistent with previous studies' findings.

The manner of use of drugs specified as "always avoid" highlights the importance of additional educational interventions designed to improve appropriate use of drugs among the elderly.

In a similar study, the CERTs used the database of a national pharmaceutical benefits manager (PBM) to examine inappropriate prescribing in a group of 765,423 outpatients age 65 or older. One in five (21 percent) of the subjects filled a prescription for one or more drugs of concern in 1999, and half of those were for drugs that carry the risk of severe adverse effects. More than 15 percent of subjects filled prescriptions for two drugs of concern, and 4 percent filled prescriptions for three or more of the drugs within the same year. These results reinforce the need to monitor prescription patterns for elderly patients more closely. The study also shows that PBM databases can be an important tool for identifying potentially dangerous prescribing patterns.

EVALUATING THE ASSOCIATION OF VITAMIN D INTAKE WITH A REDUCED RISK OF RHEUMATOID ARTHRITIS 17

Rheumatoid arthritis is one of the most common forms of arthritis and affects more than 2 million Americans, primarily women. It is a chronic, debilitating autoimmune disease in which the body's own immune system attacks healthy joint tissue, causing inflammation and joint damage.

Vitamin D plays an important role in bone health. In observational studies it has been shown to suppress the development of autoimmune diseases. In an effort to determine whether Vitamin D might help protect the body against rheumatoid arthritis, the CERTs examined data from more than 29,000 women ages 55 to 69 enrolled in the Iowa Women's Health Study. Researchers found a connection between higher levels of Vitamin D intake and a reduced risk of rheumatoid arthritis. These results support the hypothesis that Vitamin D might reduce the risk of immune disorders, and should be a subject for future research.

Effective communication between patients and providers is a vital part of delivering effective health care. The CERTs have conducted a number of studies to examine the intricacies of these relationships and to measure how outside factors affect patient care.

How physicians handle discussions with patients about medical errors has been the subject of one CERTs study. Medical errors can range in severity from mild discomfort to a life-threatening issue. The researchers surveyed a random group of 1,500 adults in a New England-based health plan to determine their attitudes toward medical error disclosure. They measured responses to questions following eight hypothetical situations, each of which had the description of a medical error, the clinical outcome of the error, and the patient-physician dialog after the event.

The survey results indicate that full disclosure of errors increased patient trust and satisfaction, and also reduced the likelihood that patients would change physicians. The survey also found that patient responses could be influenced by the details of the case and the severity of the outcome. Researchers found in some cases that full disclosure may not lessen a patient's desire to seek legal advice.

About CERTs

Annual Report Year 5

CERTs Progress

Informing Providers and Patients