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Frequently Asked Questions

The influence of nonadherence to antiepileptic drugs (AEDs) on mortality in epilepsy

Background
Epilepsy is a chronic neurologic condition characterized by recurrent seizures.1 The onset of a seizure is usually sudden and typically unpredictable. Alterations in consciousness are common and can be accompanied by motor, sensory and/or autonomic dysfunction.2 Sustained or repetitive seizure activity can be fatal; therefore, complete seizure control is the goal of therapy.1 Treatment with antiepileptic drugs (AEDs) is the cornerstone of therapy; other treatment options include dietary modifications, trigger avoidance (e.g., alcohol or sleep deprivation), implanted vagus nerve stimulators, and surgery.2

It is well established that patients with epilepsy have a significantly higher risk of mortality compared to the general population.3 Mortality may be related to the underlying pathology (e.g. a congenital brain lesion), the seizure itself, or other causes unrelated to the neurologic condition, such as pneumonia or malignancies.4 There is a bimodal distribution for mortality in epilepsy in which the underlying pathology is the major cause of death in newly diagnosed patients, and seizures are the main cause later in the course of the disease.3 Seizure-related accidents, which occur as a consequence of the seizure, can account for up to 16% of all deaths in patients with epilepsy and include motor vehicle accident (MVA) injuries, drowning, or severe burns. Patients with epilepsy can also experience sudden death. Although the exact cause of sudden death in epilepsy is unknown, it is believed to be seizure-related as well.4 One analysis reported a higher incidence of sudden death among patients with treatment-refractory epilepsy, with standardized mortality ratios for all-cause mortality ranging from 1.6 to 3.6, indicating a 60% to 360% increase in mortality compared to control populations.3

Nonadherence and seizure recurrence
One factor that can result in a lack of seizure control, a contributor to increased mortality with epilepsy, is nonadherence to AEDs.5 The incidence of nonadherence in epilepsy is reported to be between 30% to 40%, with adolescents and young adults comprising the group with the highest rate of nonadherence.6,7 A study published in Epilepsy & Behavior in 2002 evaluated the relationship between nonadherence to AEDs and seizure occurrence.8 Between July and December 2001, investigators distributed patient surveys to neurologists’ offices across the United States, to be displayed in waiting rooms and filled out by those patients with a diagnosis of epilepsy. Only patients taking AEDs were included in the study. Of the 661 responses analyzed, greater than 70% of patients reported having missed a dose of an AED at some point, and 45% of responders reported having a seizure after a missed dose. Investigators also reported that the number of tablets or capsules taken per day and dosing frequency influenced the likelihood of developing of a seizure from missed doses (p<0.01). Although the study design limited the authors’ ability to detect a casual relationship between missed doses and subsequent seizure, the data suggest a possible correlation.

Another study on nonadherence and seizure recurrence in young adults was published in Epilepsy & Behavior in 2003.7 This study, conducted between October 1996 and September 2001, used serum drug levels to monitor adherence in 52 young adult patients with a documented diagnosis of epilepsy. Patients who had taken an AED prior to the postictal blood sample or had failed to get a blood sample within 12 hours of the seizure were excluded from the study; other exclusion criteria were presence of certain seizure triggers and factors that could lower serum drug levels, such as pharmacokinetic drug interactions. A postictal serum drug level of less than 50% of the reference range (mean of 2 baseline serum drug levels) was considered nonadherence. Data were analyzed for 61 seizures, of which 27 (44.3 %) resulted from nonadherence; 22 of the 52 patients (42.3%) were classified as not adherent with their prescribed AED regimens. The authors reported a strong association between number of prescribed AEDs and incidence of nonadherence (p<0.008). It is important to note that nonadherence may have been underestimated, considering only patients who initiated postictal blood samples were followed.

Nonadherence and risk of mortality—the RANSOM study
While there is evidence to support the relationship between nonadherence to AED regimens and lack of seizure control, minimal data exist on whether or not nonadherence to AEDs increases the risk of mortality in epilepsy. Recently, the Research on Antiepileptic Nonadherence and Selected Outcomes in Medicaid (RANSOM) Study was conducted to evaluate the effect of nonadherence on mortality.5 Secondary objectives—such as rates of emergency department (ED) visits, hospitalizations, MVA injuries, fractures, and head injuries—assessed other potentially serious clinical events that could arise from loss of seizure control. The RANSOM Study was a retrospective, open-cohort study that utilized medical and pharmacy insurance claims data of 3 Medicaid programs (Florida, New Jersey, and Iowa). Patients were required to be at least 18 years of age with a diagnosis of epilepsy and at least 2 dispensings of AEDs following the diagnosis. Data collection was done throughout the specified study period (January 1997 to June 2006), until death of a patient, or termination of Medicaid benefits. Medication adherence was measured using the Medication Possession Ratio (MPR), a validated calculation used in previous studies evaluating medication adherence. The MPRs were calculated for each 90-day treatment quarter. There were 33,658 patients and over 525,000 treatment quarters included in the RANSOM Study. Twenty-six percent of the treatment quarters were deemed nonadherent (MPR < 0.8). The reported hazard ratio for mortality in nonadherent treatment quarters was 3.32 (95% CI 3.11 to 3.54), indicating over a 3-fold increase in the risk of mortality. In addition, the investigators reported a 50% increase in ED visits (incidence rate ratio [IRR] 1.5, 95% CI 1.49 to 1.52) and an 86% increase in hospitalizations (IRR 1.86, 95% CI 1.84 to 1.88). The study results also revealed an increase in the rate of MVA injuries and fractures among nonadherent treatment quarters. The results from this large, well-designed study indicate that nonadherence to AEDs was associated with serious and/or fatal events.

Summary
It is evident that nonadherence is a considerable problem in epilepsy with serious and even fatal consequences. Reasons for nonadherence are patient-specific and varied.6 Access to care, complex regimens (e.g., multiple AEDs or frequent dosing), adverse drug reactions, lack of social support, and poor patient education can all lead to patients’ inability or unwillingness to cooperate with prescribed medications. Healthcare professionals need to start by properly educating patients on their disease, the need for drug therapy, and possible adverse drug reactions. Potential barriers must be identified and strategies implemented to improve nonadherence in practice. Continued monitoring of adherence and success of implemented strategies is necessary. Clinicians should tailor the regimen to the specific needs of the patient and strive to develop the simplest, yet most effective regimen. If complex regimens are unavoidable, then such strategies as written instructions, continuing patient education, and adherence monitoring should be implemented. A partnership between the patient and clinician is crucial to the success of the therapeutic regimen, and successful regimens will improve clinical outcomes and decrease healthcare costs. In summary, these findings have important clinical implications and should advise healthcare professionals on the significance of adherence to medications for epilepsy.

References

  1. Gidal BE, Garnett WR. Epilepsy. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York, NY: McGraw-Hill; 2005:1023-1024.
  2. McAuley JW, Lott RS. Seizure disorders. In: Koda-Kimble MA, Young LY, Kradjan WA, Guglielmo BJ, Alldredge BK, Corelli RL, eds. Applied Therapeutics: The Clinical Use of Drugs. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:54.1–54.5.
  3. Lhatoo SD, Sander J. Cause-specific mortality in epilepsy. Epilepsia. 2005;46 (suppl 11): 36-39.
  4. Forsgren L, Hauser WA, Olafsson E, Sander J, Sillanpaa M, Tomson T. Mortality of epilepsy in developed countries: A Review. Epilepsia. 2005;46 (suppl 11):18-27.
  5. Faught E, Duh MS, Weiner JR, Guerin A, Cunnington MC. Nonadherence to antiepileptic drugs and increased mortality: findings from the RANSOM Study. Neurology. Published online: June 18, 2008 (doi:10.1212/01.wnl.0000319693.10338.b9).
  6. Wagner ML, Murad D, Patel D. Compliance in epilepsy: a review. U.S. Pharmacist. 2001 Aug; 26:29-30,33,36,39-40.
  7. Specht U, Elsner H, May TW, Schimichowski B, Thorbecke R. Postictal serum levels of antiepileptic drugs for detection of noncompliance. Epilepsy Behav. 2003;4(5):487-495.
  8. Cramer JA, Glassman M, Rienzi V. The relationship between poor medication compliance and seizures. Epilepsy Behav. 2002;3(4):338-342.