No Edge for Levetiracetam Over Phenytoin for Status Epilepticus

Batya Swift Yasgur, MA, LSW

May 03, 2019

Second-line treatment with the antiepileptic drug (AED) levetiracetam offers no advantage over the AED phenytoin in children with convulsive status epilepticus (CSE), new research shows.

Two studies published in the April 17 issue of The Lancet compared levetiracetam with phenytoin as second-line treatment for children whose seizures do not respond to benzodiazepines, the currently recommended first-line intervention.

The Convulsive Status Epilepticus Pediatric Trial (ConSEPT) randomly assigned 233 children to receive either levetiracetam or phenytoin and found that clinical cessation of seizure activity following the infusion of the drug took place in 50% of the levetiracetam group and 60% of the phenytoin group.

However, when the drugs were administered sequentially, the rate of seizure cessation rose to approximately 75%.

"Levetiracetam was not superior to phenytoin for the management of CSE in pediatric patients, but although both medications had considerable failure rates when given as single infusions, these failure rates could be reduced by over 50% when the two medications were given sequentially, one after the other, if children remained seizing," lead author Stuart Dalziel, MBChB, PhD, professor, faculty of Medical and Health Sciences, University of Auckland, New Zealand; and senior author Franz Babl, MD, DMedSc, professor of pediatric emergency medicine, University of Melbourne, Australia, told Medscape Medical News via email.

"This increase in efficacy of giving medications sequentially was only at the expense of an extra 10 minutes," they added.

The Emergency treatment with Levetiracetam or Phenytoin in convulsive Status Epilepticus in children (EcLiPSE) trial randomly assigned close to 300 children experiencing CSE to receive either levetiracetam or phenytoin.

No statistically significant difference between the two groups was found in either the termination of the episode or the median time to seizure cessation, although there was a trend in favor of levetiracetam in both outcomes.

"Overall, the study showed that either levetiracetam or phenytoin could be used as the preferred first-choice, second-line drug in the management of CSE in children," senior author Richard Appleton, MBBS, consultant and honorary professor in pediatric neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom, told Medscape Medical News.

"EcLiPSE is the first-ever robust and clinically relevant randomized clinical trial of any second-line drug management of CSE in children," he said.

Benzodiazepines Still First-Line

International management guidelines for pediatric CSE universally recommend benzodiazepines as first-line treatment, but they are effective in terminating CSE in only around 40%-60% of presentations, write the authors of the ConSEPT trial.

"Despite CSE being the most common life-threatening neurological emergency seen in pediatrics, there was a lack of high quality evidence to guide practice," Babl and Dalziel said.

"Prior to this study, we knew that phenytoin infusions were potentially associated with serious adverse effects and only had an efficacy of approximately 60%. Levetiracetam represented a newer and potentially safer option to phenytoin, but needed to be robustly studied," they added.

To investigate the question, the researchers conducted an open-label multicenter trial in 13 emergency departments (EDs) in Australia and New Zealand of all children in CSE (age 3 months–16 years) who presented to the ED and had failed first-line benzodiazepine treatment.

After excluding those who did not meet eligibility criteria or for whom data was not available, the researchers randomly assigned 233 children to receive either phenytoin (n = 114) or levetiracetam (n = 119).

Patients in each group were given the opposing intervention if the first was not successful in seizure cessation after 5 minutes.

The primary outcome was clinical cessation of seizure activity 5 minutes after the completion of infusion of the study drug, and the analysis was by intention to treat.

Consider Sequential Use: ConSEPT

Findings of the ConSEPT trial showed that clinical cessation of seizure activity 5 minutes after completion of infusion of study drug occurred in both the phenytoin and the levetiracetam groups (60% vs 50% of patients, respectively).

There was no significant difference in the primary outcome between patients in the phenytoin group and patients in the levetiracetam group (60% vs 50% respectively (risk difference –9.2%; 95% confidence interval [CI], –21.9 to 3.5; P = .16).

Moreover, median time to cessation of seizure from the commencement of the study drug was similar between the phenytoin and levetiracetam groups (22 minutes vs 17 minutes, respectively, difference 5 minutes: 95% CI, −13.5 to 3.5 minutes, P = 0.25).

No evidence was found for a differential effect of either drug based on age; focal vs generalized onset of CSE; febrile vs afebrile CSE; or midazolam vs other agents used as a first-line anticonvulsant.

At 2 hours, 54% of participants in the phenytoin group and 51% in the levetiracetam group maintained seizure control and did not require further anticonvulsant treatment.

When the drugs were administered sequentially, 37% of participants in the phenytoin group received levetiracetam for seizure control after phenytoin, and 40% of participants in the levetiracetam group received phenytoin for seizure control after levetiracetam.

Seizure control at 2 hours after administration of one or both study drugs was achieved without the need for further anticonvulsant treatment roughly in 78% of participants in the phenytoin group and 72% of participants in the levetiracetam group (risk difference –5.8%; 95% CI, –16.9 to 5.3; P = .31).

One participant in the phenytoin group died at 27 days because of hemorrhagic encephalitis; this death was not thought to be due to the study drug. There were no other serious adverse events.

At follow-up 1 month after hospital discharge, data were available for 86% of participants. Seizure frequency, further episodes of CSE, and proportion receiving anticonvulsants were similar between the treatment groups.

"Clinicians should consider sequential use of phenytoin and levetiracetam or levetiracetam and phenytoin, if children remain in CSE post-failure of first-line benzodiazepines," Babl and Dalziel commented.

No Robust Data

CSE treatment is guided by an algorithm recommended by Advanced Pediatric Life Support (APLS), which incorporates 10-minute intervals between treatments, the EcLiPSE authors write.

When CSE persists, either after 2 doses of benzodiazepine or the child's personalized emergency (rescue) treatment, second-line treatment is administered. However, no "high-quality evidence" supports any particular second-line treatment, the authors point out.

"I have always been interested in the evidence for how we treat children and young people with epilepsy, particularly relating to the treatment of…CSE," Appleton, the EcLiPSE study researcher, recounted.

"Its management — both under- or overtreatment with anticonvulsant medication — may result in complications, including death," he noted.

The EcLiPSE study focused on second-line management of CSE, "for which there was no previous robust data," Appleton continued, noting that the traditional or historical first-choice, second-line anticonvulsant medication used for at least the past 30 years in managing this condition has been phenytoin.

"There is a major problem with phenytoin, which is that if too high a dose is given, or the medication is wrongly prescribed or given as a continuous infusion, it may cause a cardiac arrhythmia resulting in cardiac arrest and death," he said.

Levetiracetam, one of the newer anticonvulsant medications, "seemed to be effective in the management of CSE in children and adults, with no serious side effects and certainly no cardiac toxicity," Appleton said. However, he cautioned, "all publications reporting these promising results were observational and therefore anecdotal."

"This sort of evidence is regarded as potentially biased and of low quality, and consequently would never lead to change in national practice, so consequently, I conceived of EcLiPSE [and] developed an amazing team to run the study," he recounted.

To investigate the question, the researchers assessed 404 patients and, after exclusion of those who did not require second-line treatment or did not consent, 286 children with CSE (age 6 months­–18 years) were randomly assigned to receive either levetiracetam (n = 152) or phenytoin (n = 134).

Sequential Treatment Not Justified: EcLiPSE

CSE was terminated by levetiracetam in 70% of participants, and by phenytoin in 64% of participants.

Median time from randomization to start of infusion were similar in both groups (11 minutes [IQR 8–15] for levetiracetam and 12 minutes [8–17] for phenytoin).

The infusion duration was longer than expected in 18% of levetiracetam children vs 25% of phenytoin children.

Median time from randomization to seizure cessation was shorter in the levetiracetam group vs the phenytoin group (35 minutes vs 45 minutes, respectively [log-rank test P = .20).

The unadjusted hazard ratio (HR) was 1.20 (95% CI, 0.91 - 1.60; P = .20) in favor of levetiracetam.

Of the participants in the levetiracetam and phenytoin groups, 38% and 37%, respectively, received additional anticonvulsants (relative risk [RR] 1.01; 95% CI, 0.74 - 1.36; P = .97).

Five serious adverse events were observed (3 in two participants receiving phenytoin, 1 in a participant receiving levetiracetam, and 1 in a participant who received both interventions).

Of these, 2 were assessed as related to treatment; 4 resolved; and the remaining event, which resulted in the child's death, was unrelated to either treatment.

Appleton noted that there were no statistical differences between the 2 drugs in any of the 4 secondary outcomes:

  • The need for another anticonvulsant to manage the CSE after the randomized drug had been given

  • The need for rapid sequence induction to manage the CSE after the randomized drug had been given

  • The need for admission to a critical care unit

  • The frequency of serious adverse reactions to the randomized drug

"Given the known potential fatal toxicity associated with phenytoin and the unique results of the EcLiPSE [study], serious consideration must be given to the replacement of phenytoin with levetiracetam as the preferred first-choice, second-line drug in the management of CSE in children," Appleton said.

He emphasized that, based on the EcLiPSE findings, "there is no evidence that would justify the use of both levetiracetam and phenytoin sequentially as two second-line drugs in the management of CSE in children before progressing to the next management step, which is the use of an anesthetic (rapid sequence induction)."

He added, "While it may seem attractive to use both drugs, one after the other, caution must be observed because a delay in the use of an anesthetic may be detrimental to the child with an increased risk of morbidity and mortality."

Methodological Weaknesses?

Commenting on the study for Medscape Medical News, Robert Silbergleit, MD, professor of emergency medicine, University of Michigan, Ann Arbor, who was not involved with the studies, called them "important because there are not previous high-quality data from randomized controlled trials to drive guidelines for second-line therapy for generalized CSE in the ED."

The trials "provide evidence that phenytoin or levetiracetam are both effective about half the time, but that levetiracetam was no better than phenytoin and also no safer than phenytoin," said Silbergleit, who, along with Jordan Elm, MD, Medical University of South Carolina in Charleston, coauthored an accompanying editorial .

Silbergleit cautioned that the designs of these trials "don't allow robust conclusions about non-inferiority or equivalence of the drugs, but they seem similar."

He also noted that a "major methodological weakness of these trials is that they were open label [and] the risk of bias from these 'pragmatic' unblinded designs is even greater because seizure cessation and its timing, the primary outcomes, are relatively subjective."

However, the weakness, Silbergleit said, may be "mitigated because one supposes that the investigator's bias favors a finding of superiority and they didn't find that."

He suggested several possible explanations for the similarity of the drugs across both trials.

"The obvious possibility is the hypothesis being tested — that the two drugs, at these selected doses, despite very different pharmacology, just happen to be equally effective."

It is also possible that the outcomes observed in these studies "were driven more strongly by something other than the choice of second-line drug — eg, whether and when emergency physicians give rescue medications or progress to endotracheal intubation may be driven by other pharmacological, patient, or physician factors that overwhelm the effect of the study medications," he speculated.

Appleton disagreed. "There is now good [randomized controlled trial] evidence about how to treat children with CSE that have not responded to first-line treatment, and this second-line treatment could be levetiracetam or phenytoin."

The ConSEPT trial was funded by grants from the Health Research Council of New Zealand, Auckland, New Zealand; A+ Trust (Auckland District Health Board), Auckland, New Zealand; Queensland Emergency Medicine Research Foundation, Milton, QLD, Australia; Private Practice Research and Education Trust Fund, The Townsville Hospital and Health Service, Douglas, QLD, Australia; Eric Ormond Baker Charitable Fund, Equity Trustees, Clayton, VIC, Australia; and Princess Margaret/Perth Children's Hospital Foundation, Perth, WA, Australia.

The EcLiPSE trial was funded by the National Institute for Health Research (NIHR) Health Technology Assessment Programme and sponsored by the University of Liverpool and Alder Hey Children's UK National Health Service (NHS) Foundation Trust.

Dalziel, Babl, and coauthors have disclosed no relevant financial relationships. Appleton has disclosed no relevant financial relationships. The other coauthors' disclosures are listed on the original paper. Silbergleit and Elm are both Principal Investigators of the ESETT clinical trial, which is funded by the US National Institutes of Health, with overlapping goals to the reported trials.

The Lancet. Published online April 17, 2019. Abstracts: ConSEPT study, EcLiPSE studyEditorial

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