Comparative Safety and Effectiveness of Anticonvulsants Among Older Adults

Abstract

Anticonvulsant use among older adults has increased 200-fold over the past 25 years.1 In our previous work, we estimated that one in eight older adults in the US are currently receiving anticonvulsants.2 The risk of adverse events approaches 20%, and 5% of them are potentially life-threatening.2-4 Older adults with Alzheimer’s disease and Alzheimer’s-related dementias (AD/ADRD) are more susceptible to these adverse effects.5-10 The most common indications for anticonvulsants are seizure prophylaxis, insomnia, pain, and agitation, which are all common conditions among older adults who survive an Acute Ischemic Stroke (AIS).11,12 In the US alone there are 7 million stroke survivors, and 800,000 new or recurrent stroke cases annually.11,13-15

The increasing in-hospital use of neurophysiology studies has led to greater detection of epileptiform abnormalities of uncertain clinical significance, greater perceived seizure risk, and increasing prescriptions of seizure prophylaxis with drugs like levetiracetam or phenytoin.16-19 Additionally, the rate of prescriptions of benzodiazepines for patients with post-AIS insomnia, periprocedural anxiety, and delirium (often manifested with agitation) continues to rise.2,20-23 In the meantime, major medical and psychiatric organizations suggest avoidance of anticonvulsants in those ≥65 years.2,20-28 Rigorous evidence is urgently needed about the effectiveness and safety of these drugs for older adults.5-10 However, randomized trials arguably are impractical because of large numbers needed for safety studies, the high cost of such studies, and difficulty recruiting older adults into clinical trials. Prior observational studies have severe limitations: small samples, poor data granularity and validity, selection bias, and confounding by indication. Many factors may be associated with anticonvulsant initiation, including socio-demographic, clinical, and health-care utilization characteristics.29-32

To overcome these challenges, we linked data from a prospective stroke registry (Get-With-The Guidelines-Stroke) to comprehensive electronic health records (EHRs) and applied novel statistical methods to evaluate the effects of treatment initiation strategies among adults ≥65 years who are survivors of an AIS on adverse health outcomes, initially focusing on mortality in the next months. Moreover, to enable later work toward this overall goal in national Medicare data, we conducted a validation study linking Medicare claims and EHRs to optimize claims-based definitions of AD/ADRD, an important stratification measure.

In Chapter 1, we examined the accuracy of claims-based diagnoses of AD/ADRD with respect to expert clinician adjudication using a novel database with individual-level linkages between electronic health record (EHR) and claims. A model that regressed reference standard dementia on a refined-count definition (i.e., the number of days with a qualifying diagnostic claims), and included age and sex, had excellent calibration to the reference standard with calibration-in-the-large [CV CITL] .001 and calibration slope of 0.97. The adjudicated prevalence of dementia was 7% (n=2854, 95%CI: 6%-9%) in the target population. Using a predicted probability threshold of 0.5 to classify dementia, that model demonstrated negative predictive value of 90.1% (SD 0.5%), positive predictive value of 77.1% (SD 2.0%), sensitivity of 68.0% (SD 1.8%), and specificity of 93.5% (SD 0.7%).

Next, we linked the prospective stroke registry to EHRs and examined the comparative effectiveness and safety of benzodiazepines and seizure prophylaxis initiation strategies among older adults post-AIS. In Chapter 2, we focused on benzodiazepine prescriptions, which are typically short-term (i.e., one or few doses) used to treat insomnia and agitation, and may cause serious adverse effects within few hours of initiation. In Chapter 3, we switched the focus to examine anticonvulsants given for seizure prophylaxis, which are often prescribed for 30-90 days or more, and may cause serious adverse effects within days or weeks of initiation.

Specifically, in Chapter 2, we examined the difference in 30-day mortality risk associated with initiating benzodiazepines within seven days after an AIS compared with no benzodiazepines among patients ≥65 years. We concluded that in the overall population the excess in mortality associated with initiating benzodiazepines was largely due to confounding by indication. Excess deaths per 1,000 stratified by age ranged from 2 (95% CI -16 to 12), to 12 (95% CI -9 to 143), to 20 (95% CI -43 to 81) among patients 65-74, 75-84 years, and ≥ 85 years, respectively. The RD was 1 (CI, -3 to 9) among patients with mild stroke (NIHSS ) and 18 (CI, -85 to 148) among those with moderate-to-severe stroke (NIHSS 16-20).

In Chapter 3, we examined the 90-day mortality risk associated with initiation of epilepsy-specific seizure prophylaxis within seven days after an AIS in patients ≥65 years. After standardization, the estimated mortality was 127 (95% CI, 64 to 256) and 65 (95% CI, 40 to 89) deaths per 1000 in the two strategies, corresponding to a risk difference (RD) of 62 (95% CI, -8 to 198) excess deaths per 1000 patients and a hazard ratio (HR) of 1.38 (CI, 0.60 to 3.55). Therefore, we found evidence of a potential excess in 90-day mortality associated with initiating seizure prophylaxis within seven days post-AIS compared with not initiating seizure prophylaxis in the overall population. However, the estimates were imprecise and residual confounding by indication remained a concern. In the prespecified subgroup analyses, the RD was 5 (CI, -8 to 10) among patients with minor and 88 (CI, -17 to 288) among those with moderate or severe AIS. Similarly, the RDs were 27 (95% CI -5 to 83) and 92 (95% CI -5 to 239) among patients aged 65-74 years and ≥ 75 years, respectively. The HR were similar across age and severity groups.

Our work highlights the urgent need to discuss whether older patients would benefit from or be harmed by initiation of anticonvulsant prophylaxis during the acute and post-acute stroke recovery periods. In future steps, we will examine the distribution of anticonvulsant specific outcomes as indicators of benefits (effectiveness) and harms (adverse reactions,), such as the incidence of seizure-like events and fall-related injuries and seizure-like events stratifying by care settings. We also will examine longer-term risks and benefits of other treatment indications and strategies including the comparative effectiveness and safety of specific anticonvulsants in the elderly.