ESOC 2023 | INTERACT3 results: care bundle improves outcomes in intracerebral hemorrhage

INTERACT3 is the largest ever clinical trial in intracerebral hemorrhage. It’s probably the most complex and it’s the largest using this particular design on an international scale. So, we used what’s called a stepped-wedge cluster clinical trial design where we randomize hospitals rather than individual patients, so the patients are sort of clustered within a hospital. And we analyze the data at the individual patient level, but the randomization is the hospital and all of the hospitals started off in a control phase and were randomly stepped over to implement a care bundle protocol over at least a month follow up in various phases.

So, the care bundle was a combination of early intensive blood pressure lowering, rapid reversal of hypoglycemia, rapid control of fever or pyrexia, and the rapid reversal of warfarin-related anticoagulation with a raised international normative ratio, INR. So we had we had a protocol which was with time dependent targets that had to be implemented as part of a quality control process. So INTERACT3 was quite unique in the sense that it was a discovery trial where we wanted to determine the effectiveness of this combination package of care, but it’s also an implementation study because we had to work within the hospital systems through the journey of the patient from the emergency department through ICU or surgery to the neurology ward. So it was a systems of care implementation.

We undertook the trial in over 120 hospitals in ten countries. Nine of those were low-to-middle income countries and one was high income country. And during the rollout and the clustering, we randomized over 7100 patients. We were pleasantly surprised that our primary endpoint, which was the shift in scores on the modified Rankin scale assessed at six months, was highly significant and that patients who were exposed or had the intervention, the quality improvement care bundle intervention, recovered better than those in the usual care. And in addition, there was a highly significant improvement in mortality and also changes improved quality of life, shorter stay in hospital, and less serious adverse events.

Now in doing this trial where you’re improving systems of care, it’s very important that the only change that’s occurring is the systems of care around the care bundle. You have to make sure that all levels of other aspects of care remain constant over time. So INTERACT3 had a big challenge to overcome because we started the trial at the end of 2017. We had the Covid pandemic that came in the middle of our trial and just as we were about to roll out the study across countries outside of China, we had to make some modifications to the protocol, put a pause on recruitment, slow the rollout of the study across hospitals. And so we were able to overcome that from an implementation point of view, but when we do the analysis, you need to ensure and assess and take into account any changes that may have occurred in the way in which patients were managed over time. And I’m happy to report that despite all of these challenges, there were no changes in background care detected, for example, imbalance in the way people had surgery or imbalance in the way people had ICU care or withdrawal of care. They remained constant over time. And so we are very confident that this implementation quality improvement, protocol driven intervention benefited patients in terms of their ability to survive free of disability. And this is fantastic news because in intracerebral hemorrhage everything that we’ve been doing is all level B. Level B evidence, which is probably useful and that’s because none of the trials have produced a very conclusive statistical result on the primary end point. And so INTERACT3 has now produced a conclusive level A evidence that active management protocol driven care, which is simply adopted as part of routine practice, early control of elevated blood pressure, glycemic control and pyrexia and reversal of anticoagulation. All the things that we have thought were useful have now been put together in a protocol to show that they do work. And so for the first time we should be implementing protocols for ICH.

ICH has lagged behind acute ischemic stroke where we do have lots of protocols and we do move very quickly to ensure patients are diagnosed and managed quickly. But the way in which we manage intracerebral hemorrhage does vary a lot around the world and it doesn’t generally have the same degree of urgency as acute ischemic stroke because we have had a degree of nihilism from the point of view that we’re never really sure that any particular treatment will work and therefore doctors tend to be a little bit more conservative and sometimes even introducing early palliative care measures in the belief that the patient is not going to survive and we might as well let them die quickly.