An interview with Prof. Craig Anderson, MD, PhD, Professor of Neurology and Epidemiology, University of New South Wales, about blood pressure management after intravenous thrombolysis treatment.
Interviewed by Dr. Mohammad Anadani, MD, Neurology Resident, Medical University of South Carolina.
They will be discussing the paper “Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial,” published in the February 2019 issue of The Lancet.
Dr. Anadani: First, I want to thank Prof. Anderson for agreeing to the interview. Prof. Anderson’s research has a significant impact on the stroke field and especially on our understanding of the relationship between blood pressure and outcome after hemorrhagic and ischemic stroke. Prof. Anderson was the lead investigator of the INTERACT 2 trial and the ENCHANTED trial. In this interview, we will discuss the results of the ENCHANTED trial and its implication on clinical practice.
The ENCHANTED trial addressed a very important question regarding blood pressure management after intravenous thrombolysis treatment of acute ischemic stroke. Could you please summarize the key results of the trial and to what patient population it can be applied?
Prof. Anderson: ENCHANTED was an international, multicenter, randomized, open-label, blinded-endpoint phase 3 trial that was conducted over several years to 2018. The aim was to determine whether more intensive blood pressure (BP) lowering to a systolic target of <140 mmHg would be superior (i.e., on disability according to 90-day modified Rankin scale [MRS] scores), and safer (i.e., rates of intracranial hemorrhage, including symptomatic intracerebral hemorrhage [sICH]), than the long-standing guideline recommendation of controlling BP to a systolic target <180 mmHg in patients receiving thrombolysis treatment with intravenous recombinant tPA (or alteplase). The study included over 2000, predominantly Asian, acute ischemic stroke patients with mainly mild-moderate baseline neurological severity, and whose systolic BP remained elevated above 150 mmHg after the commencement of tPA according to standard practice, and they could receive randomized BP management — intensive versus guideline — within 6 hours of symptom onset. The primary result was of no difference in the distribution (‘shift’) in mRS scores between randomized groups, with an adjusted odds ratio of 1.01 (95% CI 0.87-1.17; p=0.87]. This neutral result was confirmed in both adjusted and per protocol analyses, and across 10 pre-specified baseline subgroups that included age, ethnicity, baseline systolic BP, history of hypertension, neurological severity, and pathological type of ischemic stroke.
However, there was a large, statistically significant, lower intracranial hemorrhage in the intensive arm, while across a range of definitions of sICH, the rates were also lower, although not significantly so due to small numbers. Finally, there was no increase in serious adverse events in the intensive BP lowering group.
Interpretation of these findings, however, requires noting that the between-group difference in systolic BP of 6 mmHg over 24 hours was half of what had been planned in the sample size calculations, and likely influenced the treatment effect. This issue was due in part to many patients in the guideline group receiving BP management over 24 hours post-randomization than was expected when their BP was, by definition, already controlled (systolic <180 mmHg), and in part because most patients in the intensive group took several hours longer than the protocol goal of 1 hour to achieve a systolic target of <140 mmHg, either related to difficulties in, or clinician-apprehension over, the spend of BP control.
While these results are arguably not strong enough to support a major change in the guidelines, it would appear that clinicians have to some extent already moved beyond the <180 mmHg systolic target for BP control in this patient group, possibly due to a carry-over from guideline recommendations over BP control in acute non-traumatic intracerebral hemorrhage. However, the results certainly support the more intensive BP lowering treatment beyond the <180 mmHg systolic target as being safe, and could provide benefits from reducing the risk of serious reperfusion-related brain hemorrhage from thrombolysis treatment, albeit in ischemic stroke patients of predominantly mild-moderate severity. Yet, ENCHANTED has not fully resolved the uncertainty for what is the optimal level of BP control, or to what extent such treatment could promote recovery from ischemic stroke. Further analyses of the extensive brain imaging database from the trial are planned to understand why a reduction in sICH did not translate into overall better recovery. Moreover, until a specific trial of intensive BP lowering in ischemic stroke patients undergoing mechanical thrombectomy is undertaken, there will remain uncertainty as to the balance of potential benefits and harms in this increasingly important patient subgroup.
Dr. Anadani: The trial considered 130-140 mmHg as a systolic blood pressure target in the intensive group. Could you share with readers the rationale behind choosing this systolic blood pressure target?
Prof. Anderson: Observational studies are consistent in indicating a near linear relation of increasing systolic BP and adverse clinical outcomes in thrombolyzed acute ischemic stroke patients, from a reference of 120-130 mmHg, while the INTERACT2 study in acute intracerebral hemorrhage suggested benefits of intensive BP lowering to a systolic target <140 mmHg. A 130-140 mmHg target range was thus considered an appropriate range for optimal balance of potential benefits and harms.
Dr. Anadani: One of the safety concerns with blood pressure lowering treatment is kidney injury, especially that most patients with suspected ischemic stroke receive contrast for vessel imaging and/or digital angiography. Was kidney injury considered one of the adverse events?
Prof. Anderson: While acute renal failure was not pre-specified as an adverse outcome of ‘special interest,’ all serious adverse events were reported and centrally adjudicated for diagnosis according to standard definitions and procedures. Rates of acute renal injury were similarly very low (<1%) between the groups.
Dr. Anadani: As acknowledged in the paper, one of the limitations of the trial was the small difference in mean systolic blood pressure between the studied groups, which likely resulted from a natural drop in blood pressure after acute ischemic stroke onset. How do you think future trials should address this point?
Prof. Anderson: All recent acute and prevention trials of different intensities of BP control in areas of cardiovascular disease, including stroke, have suffered from smaller than expected BP differences between randomized groups. This is due in part because participants in the standard (control) group receive ‘better-than-usual-care’ treatment by virtue of being in research and the ‘ethical requirement’ to receive standard of care, in part because of the challenges in directing clinician behavior to manage BP more intensively than standard care in those allocated to the intensive (experimental) group. Future trials should consider: (i.) setting large BP differences, with fixed BP targets and avoiding using ‘usual care’ in controls, between randomized groups; and (ii.) including clinician investigators who have agreed and proven adherence to BP treatment protocols.
Dr. Anadani: In a post-hoc analysis of patients in the guideline group, patients treated with antihypertensive treatment had worse efficacy and safety outcomes than untreated patients. How should we interpret this finding?
Prof. Anderson: I am sure this relates to post-randomization indication bias, where clinicians treated patients of greater severity or other reason.
Dr. Anadani: How do you think the trial results would change the current clinical practice?
Prof. Anderson: I think these results will provide clinicians with reassurance over the safety of more intensive BP lowering in thrombolyzed ischemic stroke patients, certainly to systolic levels of 140-160 mmHg achieved over several hours. I am sure that many clinicians will also feel comfortable about adopting a more intensive BP control protocol with a uniform systolic target of <140 mmHg in both hemorrhagic stroke and acute ischemic stroke, albeit in those with minor deficits. Most clinicians are likely to remain cautious about rapid and intensive BP lowering in those with large cerebral ischemic deficits due to persistent concern that such treatment could worsen a large underlying ischemic penumbra.
Dr. Anadani: What advice do you have for junior investigators who are interested in further investigating the blood pressure and acute stroke research area?
Prof. Anderson: There have been considerable advances in our understanding of BP control in the setting of acute stroke over the last 10-15 years. We know that hypertension in acute stroke beyond several hours after onset is related to a larger stroke deficit with associated brain swelling but also poor pre-morbid BP control, and that lowering BP in this context does not improve the chances of recovery. In the context of acute intracerebral hemorrhage, there is reasonable evidence to indicate that good BP control improves outcomes, but uncertainty persists over the timing, speed, and preferred agent. In thrombolyzed acute ischemic stroke, there is a clear signal that intensive BP lowering reduces the risk of intracerebral hemorrhage, but we need more research to identify which types of patients could have the most to gain from such treatment. Meta-analysis of completed trials may allow an assessment of how the effects of treatment vary according to time and different patient characteristics, and more research is required to understand how the mechanisms and approaches to BP control addressing in-hospital systolic BP variability can improve outcomes.