ESETT: A Randomized Trial of 3 AEDs for Status Epilepticus

Kapur, J et al. Randomized Trial of Three Anticonvulsants Medications for Status Epilepticus. NEJM 2019;381;2103-13

This was a randomized, double-blinded, national multicenter pragmatic study to determine comparative effectiveness of traditional anti-epileptic medications in status epilepticus. The purpose of this study is to see if there is a difference between levetiracetem (Keppra), fosphenytoin (Cerebyx), and valproate (Depakote) in treatment of status epilepticus. By definition, these are second line treatments as first line treatment remains benzodiazepines (BZD). This is a well designed trial that was developed by the NIH and FDA then conducted by Neurological Emergencies Treatment Trials (NETT) and Pediatric Emergency Care Applied Research Network (PECARN). It utilized a response adaptive design to attempt to find the “best” AED (see below). Clear primary endpoint was established of seizure resolution and improving mental status one hour after starting trial medication. The protocol was guideline based as patients received cumulative BZD doses of 10 mg diazepam, 4 mg of lorazepam, or 10 mg of midazolam or weight based for children. Leaving the discussion of adequacy of those doses for another time, patients then went on to receive a weight based, unmarked vial of medication no more than 30 minutes after last dose of BZD. Dosing for these trial drugs were based off the Established Status Epilepticus Treatment Trial (ESETT) using 60 mg/kg of Levetiracetam (big doses of >4g !), 20mg/kg fosphenytoinand 40mg/kg of valproate. Protocol deviation was marked as unmasking trial drug in less than 60 minutes. 348 adults and children were enrolled into the study with interval analysis reaching a 1:1:1 trial drug administration. The primary endpoint was reached in less than half of all patients (46%) with absolutely no difference in efficacy. No difference in secondary end points such as ICU admission, median ICU stay, median ICU stay or median time to seizure termination after drug infusion. This study was not powered for to detect the rare adverse side effects but more patients that received fosphenytoin developed hypotension.

SAFETY OUTCOMES

Safety Outcome*LevitiracetumfosphenytoinValproic Acid
Hypotension0.7%3.2%1.6%
Intubation20%26%16.8%
Composite of
Hypotension
and arrhythmia
1.3%3.2%1.6%
Adverse Outcomes among the 3 AEDs
*Not powered to detect significance

Interestingly, pseudoseizure patients (~10%) were included which is clinically practical as there are times you simply do not know. 

JC Learning point: 

This trial did not have any statistical juijitsu as the primary endpoint was clear and there was no difference in efficacy. I speculate this will lead to use of levetiracetam as the go to second line agent as there is no difference to the other traditional agents which have their own respective drawbacks such as drug level monitoring, hypotension and arrhythmias as seen in rapid administration of fosphenytoin (which can easily happen in stressful situations like status epilepticus). The bigger take away for me here is 1 hour of status epilepticus is way too long for less than half the patients to improve from status epilepticus. The drawbacks of neurological damage, rhabdo and aspiration while waiting for these medications to take effect over an hour (which occurred in less than half of these patients) would be hard to stomach. As a newer emergency medicine physician, I have a tough time being patient for 15 minutes let alone 1 hour! Not to mention the longer these interventions take to have effect the more likely patients can develop super-refractory status which does not sound like fun. Bottom line, whichever second line anti-epileptic you go with, it likely does not make much of a difference in the short term as you continue to push BZD and move onto giving more BZD, intubation and propofol vs barbitutes.

Response Adaptive design

Adaptive designs allow for the review during the trial and then “adapting” the trial to allow to change the study for such changes as:

  • Abandoning treatments or doses
  • changing the allocation ratio of patients to trial arms
  • identifying patients most likely to benefit and focusing recruitment efforts on them
  • stopping the whole trial at an early stage for success or lack of efficacy.
  • Refining the sample size

In the ESETT trial the adaptive part was that at interim analysis points the drugs were evaluated and probabilities to determine if one was better (via Bayesian methods) were reviewed. If one drug was found to be worse then that arm could be dropped and the two remaining ones would stay. Thus you would get a larger sample size for the better treatment arms. Surprisingly in all the interim analyses THIS DID NOT HAPPEN. The three drugs were all found to be equally probably by the end of the trial. 

By Sagar Dave and Jesse Shriki

Stroke 2018 Update

In March New Stroke guidelines came out. Wow are they aggressive! tPA and endovascular therapy (EVT) for all… forget what the literature says! Well We NEED to know these so I’ve listed them here for reference. Sorry about the format. I’ll pretty it up soon!

Stroke. 2018;49:e46–e99. DOI: 10.1161/STR.0000000000000158.)

  1. A primary goal of achieving door-to-needle (DTN) times within 60 minutes in 50% of AIS patients treated with IV alteplase should be established.
  2. It may be reasonable to establish a secondary DTN time goal of achieving DTN times within 45 minutes in 50% of patients with AIS who were treated with IV alteplase.
  3. Systems should be established so that brain imaging studies can be performed within 20 minutes of arrival in the ED in at least 50% of patients who may be candidates for IV alteplase and/or mechanical thrombectomy.
  4. The CT hyperdense MCA sign should not be used as a criterion to withhold IV alteplase from patients who otherwise qualify.
  5. Routine use of magnetic resonance imaging (MRI) to exclude cerebral microbleeds (CMBs) before administration of IV alteplase is not recommended.
  6. Use of imaging criteria to select ischemic stroke patients who awoke with stroke or have unclear time of symptom onset for treatment with IV alteplase is not recommended outside a clinical trial.
  7. For patients who otherwise meet criteria for EVT, it is reasonable to proceed with CTA if indicated in patients with suspected intracranial LVO before obtaining a serum creatinine concentration in patients without a history of renal impairment.
  8. In selected patients with AIS within 6 to 24 hours of last known normal who have LVO in the anterior circulation, obtaining CTP, DW-MRI, or MRI perfusion is recommended to aid in patient selection for mechanical thrombectomy, but only when imaging and other eligibility criteria from RCTs showing bene t are being strictly applied in selecting patients for mechanical thrombectomy.
  9. Only the assessment of blood glucose must precede the initiation of IV alteplase in all patients.
  10. Supplemental oxygen is not recommended in nonhypoxic patients with AIS.
  11. Patients who have elevated BP and are otherwise eligible for treatment with IV alteplase should have their BP carefully lowered so that their systolic BP is <185 mm Hg and their diastolic BP is <110 mm Hg before IV brinolytic therapy is initiated.
  12. Hypoglycemia (blood glucose <60 mg/dL) should be treated in patients with AIS.
  13. IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 minutes with initial 10% of dose given as bolus over 1 minute) is recommended for selected patients who may be treated within 3 hours of ischemic stroke symptom onset or patient last known well or at baseline state. Physicians should review the criteria outlined in Table 6 to determine patient eligibility.
  14. IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 minutes with initial 10% of dose given as bolus over 1 minute) is also recommended for selected patients who can be treated within 3 and 4.5 hours of ischemic stroke symptom onset or patient last known well. Physicians should review the criteria outlined in Table 6 determine patient eligibility.
  15. For otherwise eligible patients with mild stroke presenting in the 3- to 4.5-hour window, treatment with IV alteplase may be reasonable. Treatment risks should be weighed against possible bene ts.
  16. In otherwise eligible patients who have had a previously demonstrated small number (1–10) of CMBs on MRI, administration of IV alteplase is reasonable.
  1. In otherwise eligible patients who have had a previously demonstrated high burden of CMBs (>10) on MRI, treatment with IV alteplase may be associated with an increased risk of sICH, and the bene ts of treatment are uncertain. Treatment may be
  2. IV alteplase for adults presenting with an AIS with known sickle cell disease can be bene cial.
  1. IV alteplase should not be administered to patients who have received a treatment dose of low-molecular-weight heparin (LMWH) within the previous 24 hours.
  2. Patients should receive mechanical thrombectomy with a stent retriever if they meet all the following criteria: (1) prestroke mRS score of 0 to 1; (2) causative occlusion of the internal carotid artery or MCA segment 1 (M1); (3) age ≥18 years; (4) NIHSS score of ≥6; (5) ASPECTS of ≥6; and (6) treatment can be initiated (groin puncture) within 6 hours of symptom onset.
  3. Although the bene ts are uncertain, the use of mechanical thrombectomy with stent retrievers may be reasonable for carefully selected patients with AIS in whom treatment can be initiated (groin puncture) within 6 hours of symptom onset and who have causative occlusion of the MCA segment 2 (M2) or MCA segment 3 (M3) portion of the MCAs.
  4. Although the bene ts are uncertain, the use of mechanical thrombectomy with stent retrievers may be reasonable for carefully selected patients with AIS in whom treatment can be initiated (groin puncture) within 6 hours of symptom onset and who have causative occlusion of the anterior cerebral arteries, vertebral arteries, basilar artery, or posterior cerebral arteries.
  5. Although its bene ts are uncertain, the use of mechanical thrombectomy with stent retrievers may be reasonable for patients with AIS in whom treatment can be initiated (groin puncture) within 6 hours of symptom onset and who have prestroke mRS score >1, ASPECTS <6, or NIHSS score <6, and causative occlusion of the internal carotid artery (ICA) or proximal MCA (M1). Additional randomized trial data are needed.
  6. In selected patients with AIS within 6 to 16 hours of last known normal who have LVO in the anterior circulation and meet other DAWN or DEFUSE 3 eligibility criteria, mechanical thrombectomy is recommended. (LEVEL I recommendation)
  7. In selected patients with AIS within 16 to 24 hours of last known normal who have LVO in the anterior circulation and meet other DAWN eligibility criteria, mechanical thrombectomy is reasonable. (Level IIA Recommendation)
  8. Defuse Critereia: Age 18-90 years; NIHSSS ≥ 6; femoral puncture within 6 -16 hours of stroke onset/last known well; pre- morbid mRS2≤2; ICA or M1 occlusion by MRA or CTA AND Target Mismatch Profile on CT perfusion or MRI (ischemic core volume is <70 ml, mismatch ratio is >1.8 and mismatch volume is >15 ml)
  9. Dawn Criteria: Age 18;
failed or contraindicated for IV t-PA; NIHSS ≥10; Pre-stroke -mRS 0-1; Time last seen well to Randomization: 6-24h; <1/3 MCA territory by CT or MRI; ICA- T and/or MCA- M1 occlusion;- Clinical Imaging Mismatch:
A. 80 y/o, NIHSS 10 + core <21 mL B. <80 y/o, NIHSS 10 + core <31 mL C. < 80 y/o, NIHSS 20 + core <51 mL
  10. Administration of aspirin is recommended in patients with
AIS within 24 to 48 hours after onset. For those treated with
IV alteplase, aspirin administration is generally delayed until
24 hours later but might be considered in the presence of concomitant conditions for which such treatment given in the absence of IV alteplase is known to provide substantial bene t or withholding such treatment is known to cause substantial risk.
  11. In patients presenting with minor stroke, treatment for 21 days with dual antiplatelet therapy (aspirin and clopidogrel) begun within 24 hours can be bene cial for early secondary stroke prevention for a period of up to 90 days from symptom onset. The generalizability of this intervention in non-Asian populations remains to be established, and a large phase III multicenter trial in the United States, Canada, Europe, and Australia is ongoing.195
  12. In patients with BP 220/120 mm Hg who did not receive IV alteplase or EVT and have no comorbid conditions requiring acute antihypertensive treatment, the bene t of initiating or reinitiating treatment of hypertension within the rst 48 to 72 hours is uncertain. It might be reasonable to lower BP by 15% during the rst 24 hours after onset of stroke.
  13. Routine placement of indwelling bladder catheters should not be performed because of the associated risk of catheter-associated urinary tract infections.
  14. Use of brief moderate hyperventilation (Pco2 target 30–34
mm Hg) is a reasonable treatment for patients with acute severe neurological decline from brain swelling as a bridge to more de nitive therapy.
  15. Hypothermia or barbiturates in the setting of ischemic cerebral or cerebellar swelling are not recommended.
  16. Because of a lack of evidence of ef cacy and the potential to increase the risk of infectious complications, corticosteroids (in conventional or large doses) should not be administered for the treatment of cerebral edema and increased intracranial pressure complicating ischemic stroke.
  17. Prophylactic use of anti-seizure drugs is not recommended.

Quick Hit Article #4: Aspirin NOT tPA for mild strokes – Big Pharma at it again…

Reference: Khatri P, Kleindorfer DO, Devlin T, et al. Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic DeficitsThe PRISMS Randomized Clinical Trial. JAMA. 2018;320(2):156–166. doi:10.1001/jama.2018.8496

I love me some stroke! However, nothing gets me as riled up as much as a good ole tPA for stroke study sponsored by Genentech. Look, I’m totally for thrombectomy as long as it’s done right on the right patient… I also believe in stroke centers being important to improve outcomes when caring for strokes. But haven’t we done this dance with tPA for all comers of stroke before? By my count there are 11 (if you count NINDS as 2 different studies) RCT’s of tPA for stroke. Only 2 (yes 2!) have shown benefit. So here we are now going to try to give tPA for mild non-disabling strokes? Did we forget about a little thing called brain bleeding?! Apparently so…

The Summary

This was a prospective multicenter RCT of patients with NIHSS <6 and deemed to have a “non-disabling” stroke by the clinician. Patients were given either tPA at standard dose OR 325 mg of ASA. The primary outcome end point was a modified Rankin Scale (mRS) score of 0 or 1 indicative of a favorable functional outcome at 90 days. They included all comers >18 yo without an upper age limit. The only exclusions were prior disabilities. The primary safety end point was symptomatic intracranial hemorrhage (sICH), defined as any neurologic decline within 36 hours attributed to ICH. They were to enroll 948 participants, HOWEVER, the trial was stopped early and only enrolled 313 participants. The reason cited was “Study enrollment was terminated on December 20, 2016, by the sponsor…This was a financial decision based on the fact that the trial could not be completed within the allotted funds in the specified time frame.” They say the results weren’t known. However, given the drug companies past I have a hard time believing Genetech ran out of money. At least it was still published!

THE BOTTOM LINE:

So, what were the results? There was no difference in functional outcomes between the tPA group and the ASA group at 90 days (82% vs 78%). There was a difference in the amount of ICH (3.3% vs 0%). If I were Genentech I would have stopped the study also!  So, what to do now? It’s still the same: talk to the patient, inform them of the harms and benefit. Let them know there is a risk of bleeding in the brain and not much difference in functional outcome if they just take the aspirin in low disability strokes. But please talk with the neurologist BEFORE you are in front of a patient. An argument at the time of tPA is not fair for patients. Make sure you and the stroke neurologists are on the same page.

Here’s a nice little infographic of the study:

tPA vs asa-2

 

The Details

Study Method: Prospective multicenter RCT of patients with NIHSS <6 and deemed to have a “non-disabling” stroke by the clinician The trial was designed to detect a 9% absolute difference in the proportion of participants with favorable outcome with 80% power. They used a 1-sided tail which gives the advantage to the study drug.

Exclusion criteria: Large vessel occlusion, standard tPA exclusions, and prior disability

Primary Outcome: The primary outcome end point was a modified Rankin Scale (mRS) score of 0 or 1 (total range, 0 [symptom free] to 6 [dead]), reflecting favorable functional outcome, evaluated at 90 days after enrollment and adjusted for age, time from symptom on- set to treatment, and baseline NIHSS score.

Primary Safety Outcome: The primary safety end point was symptomatic intracranial hemorrhage (sICH), defined as any neurologic decline within 36 hours attributed to ICH by local investigators; this definition was modified from the NINDS tPA trial definition requiring only a temporal association of decline with ICH.

Patients Enrolled: May 1, 2014, to December 20, 2016, 313 patients were enrolled,

Demographics:  Mean age is 62, 77% male, other than increased elevated systolic BP in the ASA group the characteristics were similar.