ESOC 2024 | TRUTH study challenges guidelines on active blood pressure lowering prior to thrombolysis

As you might know there’s a correlation between high levels of blood pressure and the occurrence of intracerebral hemorrhage after thrombolysis so, what most guidelines advocate is to lower the blood pressure with IV antihypertensive agents. However, this was never proven to be the right strategy and whereas this is adopted in most parts of the world, in the Netherlands there’s some practice variability with about 70% having the active blood pressure lowering strategy, which means that they use IV antihypertensive agents as in the rest of the world which is the prevailing practice. However, there are also centers that adhere to a protocol where they do not lower the blood pressure actively but they just wait until the blood pressure drops spontaneously below the guideline threshold and only then administer IVT. Against this background we thought it was the perfect background to investigate this problem. In practice it’s not a very common finding but about one in 10 patients that we see who are otherwise eligible for IVT have blood pressure levels above the guideline thresholds, so it accounts for one in 10 patients possibly eligible for IVT.

TRUTH was an observational multicenter, cluster-designed study in which there were centers adhering to a protocol with an active blood pressure lowering strategy, which were 27 centers, whereas there were 10 centers with no active blood pressure lowering protocol. We had a projected sample size of 1235 patients but we had to stop in 2022 because of a declining inclusion rate and because it was attributed to the COVID pandemic. But at that moment we already had included 1052 patients. Obviously since this was not a randomized trial we prespecified in the protocol paper that we would adjust for certain imbalances in baseline variables and we would also adjust for variables that we previously thought important to adjust for such as age, sex, and also stroke severity at baseline. We also had to factor in a random factor because of the cluster design so all the analyses were adjusted for these factors. At baseline there were some differences for hypercholesterolemia, the use of antiplatelets, and previous stroke/TIA which was a bit more common in the patients from active blood pressure lowering centers. The primary analysis was adjusted for that and the analysis was on functional outcome score with the modified Rankin Score which was assessed blindly by certified research nurses 3 months after inclusion. So the primary outcome was an ordinal shift on the modified Ranking Score.

As I said the baseline characteristics were well balanced except for the three variables that I mentioned earlier and what we saw, and this was somewhat contrary to our expectations, was that there was a shift towards worse functional outcome associated with active blood pressure lowering which is the prevailing practice worldwide. This shift however was not statistically significant after we performed ordinal regression analysis. In addition we did also analysis with cut offs of mRS score that were different to have binary outcomes as well and they showed very consistent results, also with the direction of the point estimate in the same direction, with worse outcome associated with active blood pressure lowering. All these results were consistent however not statistically significant.

Well I think it’s very important that we realize that the blood pressure thresholds are derived from the original trials investigating the clinical benefit of IVT. In these trials it was specifically mentioned that the blood pressure could not be lowered with the use of IV antihypertensive agents because of concerns that a rapid decline in blood pressure could compromise cerebral profusion. What we are doing in the world right now is that we do actively lower the blood pressure and we do this very fast because we want to be fast in our treatment with IV thrombolytics, however I think we should make a sort of shift which is also in line with the other studies. One of the studies presented here with blood pressure lowering already in the ambulance, the INTERACT4, which shows also a harmful effect of blood pressure lowering in the acute phase. So I think we should go back to the drawing table and consider whether we should treat these patients actively with IV antihypertensive agents at least until randomized data becomes available that this is safe and efficacious.