What is the systolic blood pressure threshold for withholding fibrinolytic therapy?

Because elevated blood pressure (BP) levels may impede the effectiveness of intravenous thrombolytic treatment with tissue plasminogen activator (tPA) in patients with acute ischemic stroke (AIS), the American Heart Association and American Stroke Association advise against the use of tPA when systolic BP reaches above 185 mm Hg.1-3 This suggested threshold, however, rests only on limited data, not on robust evidence from randomized trials. Thus, the systolic BP that could yield the best outcomes for AIS patients receiving tPA infusion remains unclear.1

Large observational studies show a correlation between high systolic BP and an increased risk of symptomatic intracerebral hemorrhage as well as a lower chance of functional independence in stroke thrombolysis, as evidenced by a 2019 systematic review and meta-analysis conducted by Konark Malhotra, MD, of the Department of Neurology at West Virginia University, Charleston Division, and his colleagues.1 At the same time, however, intensive BP lowering could hinder blood flow to the ischemic penumbra and, in turn, worsen the cerebral ischemia.2

An international study is designed

To address the issues surrounding peri-thrombolysis BP control, Craig S. Anderson, PhD, of The George Institute for Global Health, University of New South Wales, Sydney, Australia, and his fellow researchers performed a randomized trial on the efficacy and safety of aggressive versus guideline-recommended BP reduction in AIS thrombolysis.2 The trial encompassed the BP control-assessment arm of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), the results of which were reported recently in The Lancet.2 The investigators demonstrated that intensive BP management during and after intravenous thrombolysis among AIS patients, compared with guideline-recommended treatment, was associated with a reduced risk of intracranial hemorrhage, but did not lead to improved functional status.

The ENCHANTED trial, designed as a randomized, open-label trial, enrolled individuals from 110 sites in 15 countries. Thrombolysis-eligible AIS patients with systolic BP ≥150 mm Hg were randomly assigned to either of 2 treatment groups, receiving either intensive BP-lowering therapy (n=1081) or guideline-recommended BP control (n=1115) over 72 hours, with respective systolic BP targets of 130 to 140 mm Hg within 1 hour and <180 mm Hg. Functional recovery at 90 days, as assessed using modified Rankin scale scores, was designated as the primary efficacy endpoint; any intracranial hemorrhage was considered the main safety outcome.

Overall, participants’ mean age was 67 years, 38% were female, and a majority (74%) were Asian, including 65% from China. The median time from AIS onset to randomization was 3.3 hours. Mean systolic BP within 24 hours of clinical management was 144.3 mm Hg (standard deviation [SD] 10.2) in the intensive-therapy group and 149.8 mm Hg (SD 12.0) in the guideline-recommended group (P<.0001). This difference in BP was smaller than expected and didn’t reach the 15 mm Hg difference anticipated originally, the authors noted. Neurological impairment from stroke was mainly considered mild to moderate in severity: Before therapy, the median score on the National Institutes of Health Stroke Scale was 7 (interquartile range 4 to 12).

No improvement with intensive BP control

Functional status at 90 days, as assessed by trained staff in person or over the phone, did not differ significantly between patients receiving intensive BP control and those receiving guideline-recommended BP management (unadjusted odds ratio [OR] 1.01, 95% confidence interval [CI] 0.87 to 1.17; P=.8702). “This result was consistent in sensitivity and per-protocol analyses, and across key prespecified subgroups,” the authors noted.2

What might explain the nonsignificant findings for functional recovery? Else Charlotte Sandset, MD, PhD, of the Department of Neurology at Oslo University Hospital, Oslo, Norway, offered several possible reasons in an accompanying editorial.

“Acute and post-stroke hypertension is probably mainly related to premorbid hypertension rather than to a stroke-specific response,” she commented.4 In addition, the original target BP of 140 to 150 mm Hg in the intensive-therapy group in the ENCHANTED trial was changed to 130 to 140 mm Hg during the course of the study. “However, this target might have been too low,” Dr. Sandset remarked in her editorial, “causing hypoperfusion in the intensive treatment group and neutralising favourable outcomes resulting from reduced intracranial haemorrhage.”4 She also noted that the nonsignificant results may have been due to overly broad patient selection criteria.

Fewer intracranial hemorrhages observed

The risk of any intracranial hemorrhage was lower in the intensive-therapy group compared to the guideline-recommended group (OR 0.75, 95% CI 0.60 to 0.94; P=.0137). Although symptomatic intracerebral hemorrhages occurred less frequently in the intensive-therapy group, the difference between treatment groups did not reach statistical significance.2

Because study participants had strokes that were mainly mild to moderate in severity, “the study was under-powered to assess the effects of treatment on symptomatic intracerebral haemorrhage, for which the frequencies of death and major neurological deterioration were low,” the authors stated.2

The researchers observed no statistically significant difference in the number of patients experiencing serious adverse events between the 2 treatment groups (OR 0.86, 95% CI 0.70 to 1.05; P=.1412).

What should researchers do next?

“Uncertainty remains over the most appropriate timing, approach, and agent(s) for blood pressure lowering, pre-thrombolysis and post-thrombolysis,” Dr. Anderson and his colleagues wrote.2 Intensive BP management in AIS patients could “potentially reduce the risk of major intracranial haemorrhage,” but further research needs to be conducted to clearly delineate the mechanisms underlying the benefits and consequences of such treatment, the authors noted.2

They also pointed out that treatment groups with a greater difference in BP need to be studied to determine whether it’s warranted to treat patients with more-severe AIS requiring thrombolysis or endovascular reperfusion therapy.

The findings of the current study confirm that BP control after thrombolysis is important, says Dr. Sandset. “However, we still don’t know what exact BP thresholds to recommend beyond current guidelines.”

Additional multicenter, randomized, controlled clinical trials are required before the results from the ENCHANTED study can be incorporated into stroke guidelines, Dr. Malhotra suggests. “Future studies need to specifically address the optimal BP target range in acute ischemic stroke patients treated with thrombolysis,” he adds. 

“The Anderson et al trial addresses BP lowering during and after intravenous thrombolysis,” says Dr. Sandset, “and not what we should do with high BP before undertaking reperfusion treatment. Future trials should include more advanced imaging,” she continues, “as stroke is a heterogeneous disease, and it’s likely that high BP in the acute phase should be treated differently in patients with lacunar infarct than in patients with large-vessel occlusion infarcts.”

Published: May 09, 2019

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