A new study examining the effect of non-adherence to antiepileptic drugs (AEDs) on mortality rates makes clear just how dire the consequences can be — people who don't take AEDs as prescribed have a three times higher risk of death. The results underscore the need for clinicians to urge patients to take medication regularly and to discuss adverse consequences, experts not involved with the study told Neurology Today.
The study, led by Edward Faught, MD, professor and vice chair of neurology and director of the Division of Epilepsy at the University of Alabama-Birmingham, was published in the Nov. 11 Neurology.
Previous studies established the fact that people with epilepsy have a threefold higher mortality than the general population. In the current study, however, the investigators reported that non-adherence was also associated with a significantly higher incidence of emergency department visits, hospital admissions, motor vehicle accident injuries, and fractures.
Contributing factors to increased mortality include lack of seizure control, increased risk of physical injuries (fractures, burns, head injuries), and also depression and anxiety. Even AED therapy comes with additional risks — dose-related side effects, weight changes, vitamin deficiencies, and bone density loss — that increase the number of emergency department visits and inpatient care.
Until now, there have been few well-designed, data-based studies directly exploring the connection between non-adherence to AEDs and increased mortality, according to the new report.
The Research on Antiepileptic Nonadherence and Selected Outcomes in Medicaid (RANSOM) Study was a retrospective study on 33,658 patients, ages 18 and older who had at least one diagnosis of epilepsy and at least two pharmacy-dispensed AEDs.
Alan B. Ettinger, MD, professor of clinical neurology at Albert Einstein College of Medicine and director of the North Shore-LIJ Comprehensive Epilepsy Centers in New Hyde Park, NY, noted that the rates of non-adherence vary among different populations. Dr. Ettinger, who was not involved in this study but recently completed one on the prevalence and cost of non-adherence with anti-epileptic drugs in the elderly (currently in press), said that 41 percent of elderly patients are non-adherent, as are 65 percent of children and adolescents, with higher rates among those with psychiatric co-morbidity.
Many patients forget to take medication, said Mark C. Spitz, MD, professor of neurology at the University of Colorado Health Sciences Center. To help remind patients, he recommends that patients use an alarm, a pill box, and place the medicine in a conspicuous, oft-visited place, like next to the toaster if the patient uses it every morning.
But, he said, the bigger problem is with patients who intentionally do not follow the prescribed regimen. They may unintentionally miss a dose, and then when nothing adverse happens, they become confident, unconcerned, and continue to skip their medication.
Often, people knowingly skip doses because of the side effects — mostly commonly, cognitive dysfunction, fatigue, weight gain, or sexual dysfunction —which patients are disinclined to talk about.
“Men tend to be more macho and complain less and also think they can solve the problem themselves, by cutting down the dose,” he said. Physicians downplay their importance, but discussing these effects and asking leading questions are necessary because patients are reluctant to bring up this topic.
Other reasons why patients don't take medications include dementia and memory difficulties, limited formularies, transportation problems, and ambivalence about the diagnosis of epilepsy.
“Possible non-adherence should be approached in a constructive spirit; a confrontational approach may result in vigorous denial on the part of the patient and a lost opportunity for a positive intervention,” said Thaddeus S. Walczak, MD, an epileptologist at MINCEP Epilepsy Care in Minneapolis. After the patient acknowledges he or she is not taking medication, the seriousness of epilepsy, breakthrough seizures, and the possibility of death should be discussed, he said.
One strategy for helping patients adhere to the regimen, said Dr. Ettinger, is prescribing the simplest feasible plan, such as once-a-day dosing. Physicians should select AEDs with fewer pills at each dose. Also, he said, “adherence with extended release formulations may be better because of the less frequent dosing and also because variation in blood levels tends to be less extreme. If the Cmax (maximal concentration transiently in the bloodstream) is lower, there is less risk of toxic side effects, which sometimes also discourage adherence.”
When possible, neurologists should eschew technical descriptions for simple lay terms to describe the therapeutic dosing, possible drug interactions, possible adverse effects, said Dr. Ettinger, and they should give written instructions.
In addition, he suggests that neurologists foster good communication by using the “talkback” technique — asking patients to explain what they have been told to demonstrate their understanding.
“The fact that AEDs suppress seizures but do not cure epilepsy must be conveyed, and it follows that AEDs only work as long as they're taken,” said Steven C. Schachter, professor of neurology at Harvard Medical School.
Since regular follow-up with AED levels is critical, Dr. Walczak suggests setting up an organized compliance clinic at practices to reinforce adherence. Additional strategies include direct questioning during office visits or by phone, family or visiting nurse intervention, medication tablet counts, and in severe cases of non-adherence, tallying pill counts with medication event monitors (medication bottle caps with an embedded microprocessor that records the date and time of each opening of the bottle).
Of major concern is Sudden Unexplained Death in Epilepsy (SUDEP), which accounts for 10% of epileptic-related deaths. Poor medication compliance can lead to SUDEP, but this is not regularly discussed by neurologists with patients and needs to be, experts agreed.
Economic considerations — low income, high costs of drugs, and co-payments — also lead to noncompliance, and patients do not always discuss this with physicians. “I am indeed concerned about sporadic reports I hear from my patients, of holding off on refilling medications because of cost considerations,” Dr. Ettinger said. “I am hearing this kind of issue raised more and more frequently.” He added, though, that these issues have been a long-term problem and are not necessarily unique to the current economic downturn.
Industry-sponsored support programs or changing to generic medications are options, said Dr. Walczak.
The bottom line, said Dr. Schachter, is that the under-treatment of seizures has serious and sometimes fatal consequences, and non-adherence is an all-too-common cause of undertreatment. “Neurologists should consider the possibility of non-adherence if a patient's seizures do not come under control with AED therapy or worsen after a period of seizure freedom,” he concluded.