Review of Levetiracetam as a First Line Treatment in Status Epilepticus

Status epilepticus is associated with a high caste of morbidity and mortality. Approximately ⅓ of patients have long term neurologic sequela, and bloodshed is iii-v%. (Chin 2006; Raspall-Chaure 2006) First line treatment is with benzodiazepines, just benzos volition fail approximately 30-twoscore% of the time. (Appleton 2008) Therefore, an effective 2nd line agent is essential.

Despite widespread excitement nearly levetiracetam (brand name Keppra), all RCTs to appointment have indicated that information technology is no better than existing options such equally phenytoin. (Mundlamuri 2015; Chakravarthi 2015; Gujjar 2017) In fact, one trial was stopped early because levetiracetam could not beat placebo. (Navarro 2016) All the same, the previous trials were too minor to exist conclusive, and there are many theoretical arguments as to why levetiracetam should be ameliorate than phenytoin, then the ConSEPT and EcLiPSE trials were highly anticipated in the pediatrics world.

Newspaper #1: ConSEPT

Dalziel SR, Borland ML, Furyk J, et al. Levetiracetam versus phenytoin for 2nd-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial. The Lancet. 2019; http://dx.doi.org/10.1016/S0140-6736(19)30722-six

The Methods

This is a open-label, multicentre trial conducted in 13 emergency departments in Australia and New Zealand.

This was a superiority study, with the hypothesis that levetiracetam would exist ameliorate than phenytoin.

Patients

Children 3 months to xvi years in convulsive condition epilepticus who had already received 2 doses of benzodiazepine.

• Convulsive status epilepticus defined: being unresponsive with continuing abnormality of movement (increased tone or jerking) for longer than 5 min; or two or more than recurrent convulsions without recovery of consciousness between convulsions; or iii or more convulsions inside the preceding hour and a electric current earthquake.
• Exclusions: Previously enrolled in the trial, already on levetiracetam or phenytoin, received second line antiepileptics in the last 24 hours, know contraindication or allergy to a study drug, a treatment programme stating refractory to phenytoin, head injury, or pregnancy.

Intervention

Levetiracetam xl mg/kg 4 or IO over 5 minutes. (If all the same seizing five minutes after the infusion, phenytoin was given.)

Comparing

Phenytoin 20 mg/kg IV or IO over xx minutes. (If still seizing v minutes after the infusion, levetiracetam was given.)

Event

The primary outcome was cessation of seizure activity 5 minutes after the infusion of the trial drug.

The Results

They enrolled 234 patients, out of 639 candidates. 127 were missed. 278 were excluded, primarily because they were already on the study drug, or they had a treatment plan excluding phenytoin.

In that location was no difference in the master outcome. Clinical cessation of seizure activity was seen in threescore% of the phenytoin group and 50% of the levetiracetam grouping (ARR -9.ii%, 95% CI -21.nine to three.five%; p=0.16).

None of the secondary outcomes were different. (The point estimates were almost all on the side of phenytoin being meliorate).

Median fourth dimension to cessation of seizure from the kickoff of the study drug was not changed: 22 minutes with phenytoin and 17 minutes with levetiracetam (difference v min; 95% CI -13.v to 3.five minutes; p=0.25).

Adverse events were complicated, because a large proportion of the population received both study drugs. At that place were no differences between phenytoin and levetiracetam. Adverse appear to exist higher when the two drugs are combined (although that is an association only, with articulate confounders).

At that place was one death in the study. The patient was in the phenytoin group, but as well received levetiracetam, and died 27 days afterwards.

Comments on this paper

This is an unblinded trial with a relatively subjective outcome, and therefore at high risk of bias. Considering the excitement for levetiracetam (and also specifically against phenytoin) I take seen on Twitter, in papers, and at conferences, I would anticipate a clinician bias in favour of levetiracetam. They did video tape about sixty% of the patients, and blinded reviewers agreed with clinical assessments, which is reassuring.

The chosen principal effect doesn't make any sense to me. It looks at a unlike time frame for each drug because the infusion time is longer for phenytoin. It would take made a lot more than sense to look at the same time for both drugs (say 30 minutes afterwards arrival), or but try to record the total seizure time similar the did in EcLiPSE. This probably biases the primary upshot in favour of phenytoin.

In that location is a reasonable chance of selection bias, both because of missed patients, and because patients were excluded if they had a treatment plan excluding phenytoin (when no such exclusions existed for levetiracetam).

Paper #2: EcLiPSE

Lyttle Doctor, Rainford NEA, Gamble C, et al. Levetiracetam versus phenytoin for second-line handling of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open up-label, randomised trial. The Lancet. 2019; http://dx.doi.org/10.1016/S0140-6736(19)30724-X

The Methods

This is a open-characterization, multi-center randomised clinical trial at 30 Uk emergency departments.

This is a superiority trial, with the hypothesis that levetiracetam would exist better than phenytoin.

Patients

Patients vi month to eighteen years with convulsive status epilepticus (generalised tonic-clonic, generalised clonic, or focal clonic seizure).

• Exclusions: absence, myoclonic, or non-convulsive status, infantile spasms, known or suspected pregnancy, contradiction or allergy to a written report drug, known renal failure, or already received a second line anti-convulsant during this seizure.

Intervention

Levetiracetam 40 mg/kg Iv over 5 minutes (max dose 2.5 g).

Comparison

Phenytoin 20 mg/kg IV over 20 minutes (max dose 2 m).

Upshot

The chief result was time from randomisation to cessation of all visible signs of convulsive activity.

The Results

404 patients were randomized out of 1432 screened. Only 286 patients were really treated and included in the assay.

There was no divergence in the primary result of time to seizure cessation: 35 minutes with levetiracetam and 45 minutes with phenytoin (p=0.2).

There was besides no difference in the full number of patients treated successfully (70% with levetiracetam and 64% with phenytoin).

There was also no deviation in need for further anticonvulsants (37% vs 37%), RSI (30% vs 35%), or admission to critical care (64% vs 54%).

There was no departure in adverse events (12% with levetiracetam and 14% with phenytoin). At that place were v serious adverse events (3 in 2 patients receiving phenytoin, 1 in a patient receiving levetiracetam, and 1 in a patient that received both drugs).

Comments on this paper

In one case over again, this is an unblinded study with a relatively subjective upshot, so information technology is high risk for bias.

Well-nigh ⅕ of the patients in this trial had focal seizures, which probably represent a unlike course of disease, potentially requiring a different treatment algorithm. Well-nigh ⅕ of these patients were already on levetiracetam, whereas none of the patients were taking phenytoin, which could bias the results. Less than twenty% of patients screened were included, potentially limiting generalizability, and introducing selection bias.

For patients who were intubated, they "censored" the data and assumed that the time to seizure cessation was 12 hours subsequently the RSI. I am not certain that makes a lot of sense, and considering that 30-35% of the patients were intubated, a lot of the times reported in this trial are made up, which could significantly touch on the results. Given that intubation occured in 5% more patients in the phenytoin group, that could significantly increase the times reported in the phenytoin group. All times reported probably demand to exist taken with a grain of salt.

They found no difference in adverse events, merely the trial was not powered for adverse events. They try to determine which adverse events were "treatment related", but in an unblinded trial, that is unlikely to exist a reliable process.

My thoughts

These trials resulted in a lot of excited cries for levetiracetam on social media, but I think information technology is essential to highlight that these are both negative trials. These trials were superiority trials, because people were convinced the newer (more expensive drug) was going to be better, which means they were not designed to support the claims of equivalence that are now existence made. There is very petty here that suggests we should alter our standard treatment algorithms from phenytoin to levetiracetam.

Equivalence, superiority, and non-inferiority

Superiority trials are not the same as non-inferiority trials. Both of these trials were designed with the hypothesis that levetiracetam would be better than phenytoin, and both were negative. Levetiracetam is non better than phenytoin.

Because of that result, a large number of people are interpreting this trial as demonstrating that the two drugs are equivalent, but that is not what these trials evidence. In fact, I think it is pretty articulate from the numbers that if you had designed these trials as non-inferiority trials (trying to prove that levetiracetam is non inferior to phenytoin) they would have failed.

A noninferiority trial has to selection a threshold of adequate difference between the 2 drugs existence studied. With status epilepticus, that threshold should probably be pretty small, but smaller numbers need larger trials, so my estimate is that a number of 5% or 10% would have been picked. In other words, we would take been willing to accept that levetiracetam is non-inferior to phenytoin if the trial showed that information technology was not going to exist 5% worse than phenytoin (including the 95% confidence interval). Still, in ConSEPT levetiracetam was x% worse than phenytoin, with a 95% confidence interval that means it could be as much as 22% worse. And those are accented numbers! There is no way we can conclude information technology is non-junior.

A quote from that trial: "Thus, failure to find a deviation does not mean that levetiracetam is statistically equivalent to phenytoin." (Dalziel 2019)

The EcLiPSE numbers are closer. They don't present the 95% confidence intervals for the principal outcome, but the sample size is modest enough that when I run the numbers, I am pretty sure it would also have failed as a non-inferiority trial.

Of course, I am making theoretical calculations on trials not designed for those calculations. The lesser line is that it is incorrect to interpret these trials as demonstrating equivalence between these two agents. The conclusion of these trials is that levetiracetam is not better.

Outcomes

Neither of these studies looked a a truly important outcomes. Although longer seizures are associated with worse outcomes, time to seizure cessation is a surrogate outcome. One can easily imagine a drug that stops seizures earlier, but actually results in worse neurologic outcomes. Ideally, status epilepticus studies should expect at long term survival and neurologic outcomes.

If you have been following the debates on twitter, you lot will know that I remember in that location is a office for much earlier utilise of coldhearted agents, like propofol, for patients with active ongoing seizures. If you focus only on time to seizure cessation as a surrogate consequence, I think information technology is very clear that propofol will beat out both of these agents. That doesn't necessarily meant that it is better, which is why I think we need an RCT that looks at long term neurologic outcomes in these patients.

Non all condition is created equal

In my experience, in that location is a wide range of presentations of condition epilepticus. Although they are both defined as status epilepticus, at that place is a big difference betwixt a patient whose convulsions never stop, and a patient who stops with benzos merely never total wakes up, and has another seizure twenty minutes later on. I recollect those patients may crave unlike direction strategies, but both are mixed in this study population. Furthermore, EcLiPSE included patients with focal seizures, which probably also changes my treatment approach. There is as well probably a difference between a child who regularly has 25 daily seizures, and a child presenting with their first e'er seizure. I think these considerations are of import when trying to apply the results of these trials.

Harms

One of the principal concerns about phenytoin are the side effects, and especially reported deaths afterwards dosing errors. These are valid concerns, and grounded in reasonable physiology, only require careful cess. Phenytoin has been used much more widely than levetiracetam, resulting a in greater opportunity for reported adverse events, and therefore possibly biased literature.

Of notation, there was no difference at all in adverse events in these two RCTs. Although RCTs will often overlook harm, these trials were specifically looking for harms, and it is reassuring that no impairment was seen among the couple hundred patients studied. If there is impairment, information technology is likely to exist occurring in relatively pocket-sized numbers (requiring more a few hundred people in an RCT to demonstrate).

I think it is reasonable to look at observational data on the harms of phenytoin when making a decision, but we have to remember that observational data is often biased. I think it is as well important to be clear that we are choosing levetiracetam based on observational data, rather than pretending that these RCTs were strong bear witness in favour of the drug.

Convenience

Ane of the reasons for excitement about levetiracetam is ease of administration. That is an important consideration. In resuscitation, I always desire to utilise the easiest, almost foolproof medication.

Yet, I think we should be somewhat careful well-nigh our conclusions. They measured the fourth dimension to start the infusion in EcLiPSE, and it took the exact same length to become both drugs started.

People frequently worry most the length of time it takes to administer phenytoin, but administration time doesn't really affair. Fourth dimension to seizures cessation is what matters. (Equally an aside, this is one reason fosphenytoin never made much sense to me. It can be given faster, only information technology is a pro-drug, and and then time to therapeutic levels is not changed at all). These trials did not demonstrate a difference in time to seizure cessation, so who cares how long the drug takes to requite?

At that place are other reasons that levetiracetam is easier to give, but it we are going to change practice simply for convenience, we probably also demand to consider costs. According to drugs.com, a dose of levetiracetam IV volition cost most $550 USD. A similar dose of phenytoin seems to cost betwixt $xxx and $eighty USD, depending on the source. Is the convenience worth a five to 10 fold increment in price?

Not the question I would inquire

The most important thing to consider whenever assessing a trial is probably: is this the question I actually want answered? In that location is no dubiousness that we needed trials looking at levetiracetam, especially because the incredible hype this agent has in the medical community. Withal, this is probably not the question I wanted answered. Nosotros knew that 2d line anticonvulsants have a moderate effect, at best, and they all take a long time (in critical care time) to work. Leaving patients seizing for xx-thirty minutes while loading these agents never made a lot of sense to me, and numerous sources have suggested earlier use of anesthetic agents in the direction of status epilepticus. (Marik 2004; Millikan 2009; Glauser 2016) I would accept loved to come across a third arm looking at an agent like propofol.

Using fourth dimension to seizure abeyance as a surrogate, I think it is highly probable that propofol would trounce both of the agents. All the same, that doesn't hateful it is the better agent. The trial I want to run across would include a propofol arm (and maybe a ketamine arm), merely should expect at longer term neurologic outcomes. This is the most controversial of my views, and I will follow it up with its own weblog post, and probably a debate with Damien Roland, sometime in the about future.

Bottom line

Despite the excitement, these trials do not provide strong evidence in support of levetiracetam. These trials say that levetiracetam is not better than phenytoin. They also don't evidence any divergence in adverse events. This is consistent with all prior RCTs.

We should be conscientious not to merits that these trials demonstrate that the two agents are equivalent, because they do not.

I will probably continue to utilize phenytoin or valproate, until someone can evidence me any good science that demonstrates do good from this new, highly hyped agent. (Although, my treatment is often decided by local protocols, rather than pure scientific discipline). You may have other reasons to choose levetiracetam, and you should always consider all available evidence as well as your own clinical expertise when making a conclusion. There is cipher here that says you shouldn't choose levetiracetam, but it is a more expensive agent, with less overall clinical feel, and no evidence of superiority.

There isn't enough evidence to exist definitive either way, but I remain skeptical of the hype surrounding levetiracetam.

Other FOAMed

Levetiracetam versus Phenytoin for Status Epilepticus, Don't Forget the Bubbles

ConSEPT Trial: Phenytoin vs. Levetiracetam in Status Epilepsy on BroomeDocs

SGEM #265: Total ECLIPSE OF THE SEIZURE – WHAT A CONSEPT

References

Appleton R, Macleod S, Martland T. Drug management for astute tonic-clonic convulsions including convulsive status epilepticus in children. The Cochrane database of systematic reviews. 2008; [pubmed]

Chakravarthi S, Goyal MK, Modi K, Bhalla A, Singh P. Levetiracetam versus phenytoin in management of condition epilepticus Periodical of Clinical Neuroscience. 2015; 22(6):959-963.

Chin RF, Neville BG, Peckham C, et al. Incidence, crusade, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based report. Lancet (London, England). 2006; 368(9531):222-9. [pubmed]

Dalziel SR, Borland ML, Furyk J, et al. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open up-label, multicentre, randomised controlled trial The Lancet. 2019;

Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Written report of the Guideline Committee of the American Epilepsy Society. Epilepsy currents. 2016; 16(1):48-61. [pubmed]

Gujjar AR, Nandhagopal R, Jacob PC, et al. Intravenous levetiracetam vs phenytoin for condition epilepticus and cluster seizures: A prospective, randomized study. Seizure. 2017; 49:viii-12. [pubmed]

Lyttle MD, Rainford NEA, Take chances C, et al. Levetiracetam versus phenytoin for 2nd-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial The Lancet. 2019;

Marik PE, Varon J. The management of status epilepticus. Chest. 2004; 126(2):582-91. [pubmed]

Millikan D, Rice B, Silbergleit R. Emergency treatment of status epilepticus: current thinking. Emergency medicine clinics of North America. 2009; 27(ane):101-xiii, ix. [pubmed]

Mundlamuri RC, Sinha South, Subbakrishna DK. Management of generalised convulsive condition epilepticus (SE): A prospective randomised controlled written report of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam–Pilot study. Epilepsy enquiry. 114:52-8. 2015. PMID: 26088885

Navarro V, Dagron C, Elie C. Prehospital handling with levetiracetam plus clonazepam or placebo plus clonazepam in condition epilepticus (SAMUKeppra): a randomised, double-bullheaded, phase 3 trial. The Lancet. Neurology. xv(one):47-55. 2016. PMID: 26627366

Raspall-Chaure M, Mentum RF, Neville BG, Scott RC. Outcome of paediatric convulsive status epilepticus: a systematic review. The Lancet. Neurology. 2006; 5(9):769-79. [pubmed]

Cite this article as:
Morgenstern, J. Levetiracetam versus Phenytoin in Condition Epilepticus (ConSEPT and EcLiPSE), First10EM, April 21, 2019. Available at:
https://doi.org/10.51684/FIRS.8416

villanuevaingents.blogspot.com

Source: https://first10em.com/consept-and-eclipse/

Share this post