A Randomized Trial of Brief Versus Extended Seizure Prophylaxis After Aneurysmal Subarachnoid Hemorrhage (DOPAST) , by Theresa Human et al.
Subarachnoid hemorrhage (SAH) is a nightmare. I mean, the real ones. Blood everywhere, delayed cerebral ischemia (DCI), more blood, intracranial hypertension, death… and in the middle of all this, sometimes, seizures. That’s an interesting topic. We think we know something about it, but the fact is, we don’t know shit. I mean, of course we have some trials and all, but like in TBI, seizures, specially seizure prophylaxis is still under construction. And that’s why it’s so interesting! Where is the fun in discussing aspirin for MI? None! You just give it and lives are saved. Now, discussing seizure prophylaxis is fun everywhere, from TBI to SAH! Why am I saying this? Yeah, that’s why: A Randomized Trial of Brief Versus Extended Seizure Prophylaxis After Aneurysmal Subarachnoid Hemorrhage!
But as usual, first things first. We’re only going to discuss SAH from aneurysmal rupture! So, let’s play a mental game of suppositions before we really start: Let’s suppose SAH increases the risk of seizures, both acute and long term, and the seizures itself are responsible for poor neurological outcomes in the future. Would I improve the outcomes if I prevent seizures in the acute setting? Right off the bat? I would say no. And here is why:
It seems SAH in fact increases the risk of seizures. A population study showed that 15% of SAH patients without previous epilepsy will have at least 1 seizure in the first week after SAH, with a cumulative incidence of epilepsy in 5 years of 12%. Another study showed that in hospital seizures occurs in 7% of SAH patients, with at least 1 seizure occurring in 11% of patients after hospital discharge and 7% developing epilepsy. Intraventricular hemorrhage and poor Hunt and Hess grades (III/IV) appeared to be risk factors in one study, while subdural hematoma and cerebral infarction were in the other. Both studies stated that development of epilepsy was associated with poor neurological outcomes. A sub-study of the ISAT trial showed a risk of epilepsy at 5 years ranging from 6.4% (endovascular group) to 9.6% (neurosurgical group), with DCI, thromboembolic complications and neurosurgical treatment as risk factor. OK, SAH appears to increase the risk of seizures. But woudn’t seizures be a marker of disease severity, instead of a causal pathogenic mechanism? That’s the point. Wouldn’t seizure be the “lactate” of SAH? Well…I leave such judgements to you guys.
Suppose all of that is true, and indeed, seizure itself is the villain here. Now, believe if I decrease the number of acute seizures by giving prophylaxis, would it interfere in a more chronic process and improve neurological outcomes in the future is a whole new ball game! Do we have any good evidence to support that? No! And that’s not a bad thing. Well, I wish we had the evidence, but there is where opportunity lies. New and better evidence. That was the idea behind DOPAST trial. However, although the lack of evidence in giving seizures prophylaxis for SAH, the practice around tells us a different story. A survey (25 USA academic centers) showed that 68% of responders routinely use anticonvulsants for seizure prophylaxis. The first line medication was levetiracetam (94%), while the good (not so good) old phenytoin was used in only 4%. That’s another interesting point: why is everybody using levetiracetam(LEV)? A small, single center, single-blinded trial (52 patients) comparing LEV vs phenytoin (PHT)  (to be honest it was more of an exploratory trial, without any defined primary outcomes and a LOT of comparisons) for seizure prophylaxis (both TBI and SAH patients) showed patients in LEV group had better neurological outcomes in 3 months, although there were no differences in seizures (both acute and in 6 months). While other trial in SAH patients showed LEV had superior tolerability compared to PHT regarding side effects. You can argue the use of PHT is associated with worse neurological outcomes  in SAH patients, that’s why LEV is a better choice. I can’t argue against that since there is no evidence to support neither PHT, nor LEV, for seizures prophylaxis in SAH.
How they did it
After this preamble, off to the trial we go! Instead of comparing seizures prophylaxis with no-prophylaxis, the authors decided to compare “whether an extended course of LEV (until hospital discharge) was superior in preventing in-hospital seizures than a short (3-day) course”. It was a single center, pragmatic, randomized trial. Inclusion criteria were: aneurysmal SAH and ≥18y/o. Patients with history of epilepsy were excluded. Primary outcome was seizures during hospitalization. Electroencephalogram (EEG) was performed only when indicated by the physician. The sample size was calculated based on a baseline seizure rate of 8.3% in the short duration group compared to 3.4% in the extended duration, with 60% of power (Jesus, 60%!) and alpha level of 5%, giving a total of 400 patients.
Unfortunately, due to slow recruitment, the study was halted after 84 patients were enrolled. This early stop led to unbalanced groups (they were using block randomization). The table below shows the characteristics of both groups.
Unbalanced as I said. Worth noticing around 24% of all patients had poor grade WFNS (IV-V) and 60% had external ventricular drain due hydrocephalus. More patients in the short group had seizures prior to admission (23% vs 14%). There was no difference in ICU or hospital LOS. The extended group received LEV for a median of 14 days (IQR 10–20) compared to 3 days (IQR 2–3) in the short group. One patient in the extended group (2%) had an in-hospital seizure compared to three patients (9%) in the short group (p=0.2), and needles to say the study was underpowered. All 4 seizures occured after day 3, and 20% of patients in the extended group had LEV discontinued prior to hospital discharge (mostly due to sedation). They couldn’t find any clinical or radiographic SAH scores associated with increased risk of seizures. Patients in the extended group had higher risk for poor functional outcomes (OR=4.7, 95% CI 1.1–20.2, p = 0.036) after adjusting for covariates.
In the end
So, what does this trial tells us? First: it’s bloody hard to enroll patients in SAH trials. For example, the ISAT trial  enrolled patients from 1994 to 2001 in 43 centers, therefore 84 patients in 4 years in this tiral is not a bad result. Second: it’s hard to take this trial’s results and put them into practice. As usual, larger multicenter trials are needed. But an interesting discussion is what are the questions these future trials should be asking? Long term neurological outcomes would be my choice. After a brief search at clinicaltrials.gov I couldn’t find any registered research on this matter. Until then, what to do? Well, seizure prophylaxis for patients with SAH and unprotected aneurysms seems reasonable for me, specially for patients with risk factors (although we don’t really know what those factors are). For the rest? My answer is no. Not until better evidence is available. We don’t even know which drug to use! Let’s stop with this paranoia of giving prophylaxis to everything, unless good evidence tells us otherwise.
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