ESOC 2023 | Initiating anticoagulation after ischemic stroke: a review of the evidence

I will be talking about initiating anticoagulants since we lack randomized data. Most of the trials, all the trials that have proven the efficacy of anticoagulation in preventing stroke recurrences either excluded patients with moderate or severe stroke or included them months after the index event. So we lack data from randomized trials on the subacute phase of stroke. We also know that the first days after stroke are the most crucial and they carry the most risk of recurrent stroke. So it is plausible to ask ourselves if we go and start anticoagulation earlier in order to reduce these events. We also know that the first month after stroke in these patients, patients with cardioembolic stroke, there is a non-negligible risk of intracranial hemorrhage, late hemorrhagic transformation. So this should be done safely. So all the controversy is about the optimal time that is both safe and efficient to start anticoagulants.

Now we have data from observational studies. We have data from the RAF-NOACs registries. We know that there are different types of anticoagulation, of course, and we have different type of data for each of the of the molecules used. For example, we know the results of the MR CLEAN-MED trial that used very early anticoagulation. In fact, they have started anticoagulating patients during endovascular treatment with heparin and continue that for some hours after endovascular treatment. And as you may well know, this trial was halted since the treatment group with high heparin and aspirin had greater risk of hemorrhagic transformation. So we also know for NOACs, with the RAF-NOAC study, that when we start them in the first two days after stroke, there might be a bleeding risk. And we have seen the publication of a couple of randomized control trials. One such trial is the Triple AXEL study that has tested rivaroxaban and vitamin K antagonists in the first five days after stroke. This is a stroke group not specifically targeted at endovascular treatment patients since for these patients we even have less data. Well, the Triple AXEL study showed that it’s quite safe to start earlier, but this study excluded severe strokes. When we are talking about endovascular treatment patients, there are patients with more severe strokes with larger infarcts. So these are the patients that are both prone to bleeding and also more susceptible to have recurrent stroke.

Now specifically for endovascular treatment, in the TIMING study, which was a Swedish randomized control non-inferiority study, registry based, there was a 14% of patients having EVT. But specifically for them we have some observational data coming for a subgroup Japanese cohort study, the RELAXED study that has shown also that it might be safe, it might also be more efficient to start earlier. Now for the group that we have, the least available data is the patients that have early hemorrhagic transformation. So they have some kind of bleeding in the first 24 hours after stroke. For these patients, we only have a couple of observational studies, one from China and another from Japan, that show that we can start earlier, but in the first four days, the Japanese study raised a red flag that showed that there might be an excess risk of bleeding.

It is of importance that we will see tomorrow during the first day of ESOC Congress, the results of the ELAN trial, which is a randomized control trial of early anticoagulation initiation and it concerns all stroke patients and it has used the approach of clinical neuroimaging. So you might decide when to start anticoagulants based solely on clinical grounds. So NIHSS stroke severity, this is the approach used by the American guidelines and the guidelines issued by the European Society of Cardiology, or you might use a combined approach of clinical and neuroimaging data, which is the approach used by the European Stroke Organization guidelines. ELAN trial has used this approach to randomize patients and it would be of great interest to see their results.

There are some things where we are certain about or we are almost certain. Full dose heparin during endovascular treatment carries increased risk of bleeding. It’s still being used especially for stent deployment in the context of intracranial atherosclerotic disease. So the fact that it’s still being used means that it’s necessary sometimes. The dose is important, so we should probably go as low as achievable or reasonable for heparin in the acute phase. The other thing that we know is that NOACs are more safe and efficient in the subacute phase after stroke and we have performed, our study group, a systematic review and meta-analysis showing that, that NOACs carry less bleeding risk and also are more efficient.

Bridging is no longer an option. So bridging to remind you is giving full dose heparin before starting oral anticoagulation. We have multiple data from the IAC studies and other studies also showing that bridging is deleterious so you don’t need bridging. You go straight ahead with NOACs in the subacute phase. Now the exact time is related of course, to the severity of the infarct, to the extension of the infarct, and whether you have an hemorrhagic transformation or not. So for patients with minor infarcts, you may start in the first days. For more severe infarcts within the first week. For parenchymal hemorrhage, you should probably wait for the second week. But the final conclusion is that within two weeks after stroke, most patients should receive anticoagulation. All data converge towards the fact that most patients should be treated within two weeks because it is quite safe. NOACs are safe as far as intracranial hemorrhage is concerned and we reduce the risk of recurrences.