ARTICLE IN BRIEF:
A large phase 3 study found that intensive blood pressure lowering to targets below those recommended by guidelines safely reduced the risk of intracranial hemorrhage as a side effect in stroke patients but did not limit post-stroke disability at 90 days.
HONOLULU—Lowering high blood pressure in those with hypertension has been a guideline-recommended goal, but when it comes to stroke risk, how low should systolic blood pressure go, and will it help or harm patients who undergo thrombolysis with clot-busting drugs?
The was the question an international randomized trial attempted to answer—and the results were a mixed bag of news. Functional outcomes after an ischemic stroke treated with clot-busting drugs were not helped by a program of intensive blood pressure lowering—the goal of which was to lower systolic blood pressure below 140 mmHg— when compared to standard of care hypertension treatment, researchers reported here at the 2019 International Stroke Conference. But at the same time, they found that intensive blood pressure control reduced the risk of intracranial hemorrhage. The results of the study were published in the February 6 online edition of The Lancet.
The treatment effect at 90 days seen in the Enhanced Control of Hypertension and Thrombolysis Stroke (ENCHANTED) study was minimal and not significant in terms of stroke-related disability, reported Craig S. Anderson, MD, PhD, professor of neurology and epidemiology at the University of New South Wales, Sydney, Australia, and executive director of The George Institute in China.
But the key safety outcome of the trial was positive, as intracranial hemorrhage, a worrisome consequence of the use of tissue plasminogen activator (tPA) in breaking up clots, was significantly reduced in the ENCHANTED population, Dr. Anderson said.
Study Design, Findings
The ENCHANTED study was an international, multicenter, randomized trial, which involved 110 sites in 15 countries. Patients were managed in an acute stroke unit, and non-invasive blood pressure monitoring was done using an automated device applied to the non-hemiparetic arm, with the patient resting supine for at least three minutes in accordance with standard protocols. Following thrombolysis, blood pressure measurements were recorded every 15 minutes for one hour, hourly from hours one to six, and six times hourly from hours six to 24.
Subsequently, blood pressure was recorded twice daily for one week (or until hospital discharge or death, if earlier). The investigators assessed neurological status using the National Institutes of Health Stroke Scale and Glasgow Coma Scale at baseline and 72 hours after starting alteplase treatment. They also did brain imaging at baseline, at 24 hours, and additional timepoints, if clinically indicated.
In the unadjusted primary outcome, the odds ratio of having a better shift in the modified Rankin Scale was 1.01 (p=0.8702), Dr. Anderson reported at the International Stroke Conference. When researchers adjusted the results to account for baseline characteristics, the results weren't much different (p=0.7171), he said. And when the outcomes were adjusted for per protocol adherence, there still was a neutral result (p=0.5141), he said.
Among the 1,081 patients treated with intensive blood pressure lowering, 59 patients experienced intracranial hemorrhage—about 5.5 percent of that group—while 100 of the 1,115 patients, or 9 percent, of those assigned to standard therapy for blood pressure control, experienced intracranial hemorrhage (p=0.0017).
“This study clearly shows intensive blood pressure lowering has the potential to make thrombolysis treatment safer by reducing the risk of serious bleeding in the brain,” Dr. Anderson said.
Possibly confounding the results of the study was that blood pressure lowering was substantial in both groups. Although the goal in the standard of care group was to lower blood pressure to 180 mmHg over a three-day period, clinicians were able to reduce blood pressure in that group to a mean of 144 mmHg, while the patients on the intensive treatment—where the aim was to lower systolic blood pressure below 140 mmHg—the mean blood pressure was 139 mmHg.
“These findings also highlight the need for more research to better understand the underlying mechanisms of benefit and harm of early intensive blood pressure lowering in the patients receiving modern reperfusion therapy with thrombolysis and devices, given that the reduction in brain hemorrhage failed to translate into improvements in overall recovery for patients,” said Tom Robinson, MD, BMBS, head of the Cardiovascular Research Centre at the University of Leicester, United Kingdom, and a co-author of the ENCHANTED trial, who also presented the results.
“Many clinicians are concerned that rapid blood pressure reductions in the absence of mechanical or pharmaceutical reperfusion might worsen cerebral ischemia from potential hypoperfusion with compromised autoregulation and collateral flow,” the study authors wrote in The Lancet.
“In our trial, any benefit from intensive blood pressure reduction on outcome due to reduction in intracranial hemorrhage might have been offset by hypoperfusion of the ischemic penumbra. However we observed no significant heterogeneity of treatment effect in subgroups where large vessel occlusion might be anticipated, including acute ischemic stroke subtypes classified on the basis of clinician-diagnosis of large vessel disease, cardioembolic, or lacunar acute ischemic stroke, and in post-hoc analysis of stroke severity based on quartiles of increasing NIHSS score.”
Commenting on the study, Ralph L. Sacco, MD, MS, FAHA, FAAN, chairman of neurology, Olemberg Family Chair in Neurological Disorders and Miller Professor of Neurology Public Health Sciences at the Miller School of Medicine at the University of Miami in Florida, told Neurology Today: “These were all patients treated with intravenous tPA within 4.5 hours—so it was a normal treatment, but we wanted to know if we should be more aggressive in the early control of blood pressure versus what the guidelines currently say, which is to get the blood pressure down to less than 180 mmHg. The guidelines suggest that if you get the blood pressure below 180 mmHg, then it may be safe to give tPA.”
“The question was, could we do even better to stop bleeding if we lowered the blood pressure even more tightly controlled to 130-140 mmHg further,” Dr. Sacco said. “While there was no difference in disability at 90 days, there was less bleeding; even though there was just a small difference in blood pressure it still made a difference in bleeding. The most feared complication of using tPA is intracranial hemorrhage and lowering blood pressure seemed to lessen this complication in the ENCHANTED study.”
“In this trial the guideline group did better in lowering blood pressure than you would have expected. It seems that people are being more aggressive with blood pressure control, and that may be why we didn't see a difference in disability outcomes,” he said. “The benefit we saw in safety did not seem to translate into a benefit in function.”
Dr. Sacco noted, however, that one should be cautious in delaying treatment with tPA in order to get the patient's blood pressure lower. “At this point, I would say there probably is no reason to change the guidelines, especially since people seem to be practicing aggressive blood pressure lowering anyway,” he said.
In an editorial in The Lancet, Else Charlotte Sandset, MD, PhD, professor of neurology at Oslo University Hospital, and Urs Fischer, MD, professor of acute stroke at Bern University Hospital in Switzerland, noted, “ENCHANTED is the first, to our knowledge, large randomized trial to investigate blood pressure management in the setting of intravenous thrombolysis for acute ischemic stroke, and adds important evidence. Notably, intensive blood pressure management reduced the risk of intracranial hemorrhage but did not improve functional outcome.”
“This finding,” they wrote, “might be related to the smaller than envisaged difference in blood pressure between the groups, or the inclusion of mainly patients with mild-to-moderate stroke, who are less likely to develop symptomatic intracerebral hemorrhage. However, this new evidence is somewhat disenchanting. Like other large trials, ENCHANTED showed a neutral effect of blood pressure lowering on functional outcome in acute stroke.”
The authors of the editorial suggested that further trials are still warranted, but with some tweaks. “Such trials should select patients on the basis of pathophysiological considerations (i.e., vessel imaging and perfusion studies), and test whether blood pressure should be lowered after rather than before recanalization therapy in patients with large vessel occlusion,” they said.
“As clinicians, we are treating individuals: Thus, more evidence for individualized treatment approaches is needed. The use of advanced imaging—the most relevant biomarker in acute stroke management — should be implemented in future randomized controlled trials of blood pressure lowering in these patients to better understand the underlying mechanisms of benefit or harm related to treatments under investigation,” they reported.
The National Health and Medical Research Council of Australia and the UK Stroke Association and others funded the ENCHANTED trial. Takeda also supported the study in China.
Dr. Anderson received a research grant from the National Health and Medical Research Council of Australia and research funds from Takeda for support of the trial in China. He serves on the advisory boards of Boehringer Ingelheim and Amgen. Dr. Sandset was a visiting fellow at the George Institute for Global Health, under the mentorship of Dr. Anderson in 2019, and a visiting fellow under the mentorship of coauthor Philip Bath in 2014. She also has received speaker's fee from Bayer and Novartis unrelated to this work. Dr. Fischer receives consulting fees from Medtronic, Stryker, and CSL Behring.