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WSC 2022 | ENCHANTED2: intensive blood pressure control after successful reperfusion for acute ischemic stroke

Craig Anderson, PhD, University of New South Wales, Sydney, Australia; Lili Song, MD, PhD, The George Institute for Global Health China, Beijing, China; Pengfei Yang, MD, Changhai Hospital, Naval Medical University, Shanghai, China; and Jianmin Liu, MD, Changhai Hospital, Naval Medical University, Shanghai, China, share the findings of the ENCHANTED2 trial (NCT04140110) assessing the safety and effectiveness of intensive blood pressure (BP) lowering after mechanical thrombectomy for acute ischemic stroke. Previous evidence from ENCHANTED (NCT01422616) suggested that intensive BP lowering may reduce intracranial hemorrhage occurrence, but this reduction did not lead to improvements in functional status. ENCHANTED2 therefore aimed to shed light on intensive BP control as a strategy to improve clinical outcomes, assessing functional recovery at 90 days as the primary study endpoint. The trial recruited more than 800 patients with persistent hypertension (systolic BP ≥140mmHg) who underwent successful reperfusion therapy after an acute ischemic stroke due to large vessel occlusion. Participants were randomized 1:1 to more-intensive (target SBP ≤120mmHg within 1 hour) or less-intensive (target SBP 140-180mmHg) BP management over 72 hours. Recruitment was suspended in June 2022 due to safety concerns in the more-intensive BP management group. More intensive BP lowering was shown to be associated with worse functional outcomes and more early neurological deterioration, compared to less intensive BP control. These data will have an impact on clinical practice, emphasizing that 120mmHg is the lower safety margin and BP lowering efforts should not go beyond this. While these findings have narrowed the goal window, questions remain on the optimal target for BP lowering. This interview took place at the World Stroke Congress 2022 in Singapore.

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Transcript (edited for clarity)

Craig Anderson:
Hello, my name’s Professor Craig Anderson from the George Institute for Global Health in Sydney, Australia. And it’s a great pleasure to outline our study, the ENCHANTED2 MT clinical trial, which was evaluating early intensive blood pressure lowering in patients who have had successful reperfusion with endovascular clot retrieval for acute ischemic stroke from large vessel occlusion...

Craig Anderson:
Hello, my name’s Professor Craig Anderson from the George Institute for Global Health in Sydney, Australia. And it’s a great pleasure to outline our study, the ENCHANTED2 MT clinical trial, which was evaluating early intensive blood pressure lowering in patients who have had successful reperfusion with endovascular clot retrieval for acute ischemic stroke from large vessel occlusion. We’ve known for a long time that if you present with an acute ischemic stroke and have high blood pressure, you have a bad outcome. We’re not certain of the mechanisms. Maybe the high blood pressure may make you more prone to bleeding as a consequence of reperfusion treatment or as a result of the success of reperfusion. Because blood pressure is readily modifiable, it makes sense to examine whether we can improve clinical outcome, reduce reperfusion harm or reperfusion complications with early intensive blood pressure lowering.

There has been some trial evidence to date to suggest that it’s safe. There is a signal in reducing bleeding. But we don’t have definitive evidence as to whether it improves recovery. So we embarked on the ENCHANTED2 MT clinical trial to resolve this uncertainty. People who present with an acute ischemic stroke from large vessel occlusion who’ve had successful opening up of the occluded blood pressure and remain hypertensive, whether a more intensive blood pressure control to a less than 120 systolic target versus a more conservative level, which is between 140 and 180, would improve clinical outcome. I will pass over now to the project leader in China, Dr. Lili Song to give you an outline of the study design. Lili?

Lili Song:
Thank you very much. My name is Lili Song. I’m working with Professor Anderson for many years, and I’m also the Head of Stroke at the George Institute, China office. And I’m the main research fellow for this project. So ENCHANTED-MT is an investigative initiated, multicenter, pragmatic, prospective, randomized, open label, blended endpoint -also called PROBE- trial. This study aimed to determine the effectiveness and the safety of more intensive blood pressure control following successful reperfusion after endovascular thrombectomy in patients with acute ischemic stroke due to large vessel occlusion.

The patients who met eligibility criteria were randomized at one-to-one ratio to either more intensive blood pressure lowering group with systolic blood pressure target of less than 120mmHg within one hour after randomization and maintain this blood pressure level for 72 hours. Or to less intensive blood pressure lowering group with systolic blood pressure target of 140 to 180 for 72 hours. All randomized, the patients will receive best medical care according to local guideline recommendations. The primary outcome of this study is a functional recovery at 90 days assessing by ordinal shift analysis of scores on the Modified Rankin Scale.

The patient’s demographic, clinical, and imaging data were collected at the day one, day seven. And the endpoints were assessed by telephone or in person at 90 days after randomization. The original sample size was 2,257 which provides 90% power to detect a moderate effect of 60.5% absolute reduction in poor outcome. So that’s the study design.

Pengfei Yang:
So I’m Pengfei Yang from Changhai Neurovascular Center of Shanghai Naval Medical University. I’m also the researcher in this ENCHANTED2 MT trial. Our ENCHANTED2-MT trial is the largest MT controlled trial for patients after successful mechanical thrombectomy until now. We have enrolled more than 800 patients, and our study was stopped early by DSMB due to safety concern. The primary result showed that more intensive blood pressure lowering to less than 120mmHg was associated were with worse functional outcomes when compared with less intensive BP control to 140. And this adverse effect emerged within seven days. The more intensive group has more early neurological deterioration. However, there were no significant differences in symptomatic intracerebral hemorrhage. For all the pre-specified subgroups there was no heterogeneity on the primary outcome. I would like to hand this over to Professor Jianmin Liu. He’s Director of our department. He will talk about the implications for clinical practice in China.

Jianmin Liu:
Okay. So current guidelines recommend control blood pressure to less than 180. So this is very broad range without a special target. So our trial showed that the intensive blood pressure control with a target of less than 120 should be avoided in clinical practice. It gives the physician a very clear, low threshold of BP control. ENCHANTED2 was formed in 44 centers of China. All patients are Chinese. So I believe it will definitely impact Chinese physicians’ practice. So Professor Anderson?

Craig Anderson:
Yeah. So look. The implications in the trial outside of China are very consistent. We had a very strong definite result over harm. So that’s going to cause people to be rather cautious around the degree of blood pressure lowering. So I think we can be very certain now that we have to be careful with the monitoring blood pressure that we don’t have it too low. So I think that’s now pretty certain that the 120 systolic cut point is the safety margin. But what we don’t know is what is the optimal. We’ve had other studies to suggest a 140 might be beneficial. And now we’ve shown if we go too low, it’s harmful. But there’s still this window. What is the optimal level? Should it be 130? Should it be 125? Should it be 140? So there’s still room for the research to come up with the direct evidence to guide us.

The other thing is that it’s very important that we can tailor our therapy, tailor our treatment, and there may be particular groups of patients that are more beneficial or more at risk that we need to know about. So there’s more work that we need to do within our own study to look at the brain scans to better understand the degree of ischemia, the degree of blood flow. And we also need to work with other investigators who are doing similar studies in other parts of the world to share data so that we have more information about particular subgroups of patient characteristics. So we’ve certainly advanced knowledge. But we haven’t resolved all of the questions. And this has certainly helped us to move the information forward on how best to manage blood pressure in this particular serious type of acute ischemic stroke. Those who present with large vessel occlusion where we have a treatment but we still don’t have a perfect treatment, and where blood pressure control may be a very potential useful mechanism to help support recovery from this dreadful condition. Thank you for listening.



Craig Anderson: grant funding from the National Health and Medical Research Council (NHMRC) of Australia, the Medical Research Futures Fund (MRFF) of Australia, Takeda China, Penumbra, and the Medical Research Council (MRC) of the UK, all paid to institution.
Lili Song: funding and lecture fees from Takeda China.
Pengfei Yang: funding from Shanghai Changhai Hospital and honoraria for lectures from Stryker, Medtronic, Microvention, and Cerenovus.
Jianmin Liu: grants from the China Stroke Prevention Project and the Science and Technology Commission of Shanghai Municipality.