Blood pressure treatment in acute ischemic stroke: an elusive target

An optimal target for blood pressure (BP) management in acute ischemic stroke (AIS) to achieve the best functional outcome remains uncertain. Current practice is mostly guided by the avoidance of extreme values.

On one hand, the ESO guidelines on intravenous thrombolysis (IVT) recommend achieving and maintaining a BP value <185/110 mmHg before and 24-hours after administering IVT. The recommendation is based on observational data suggesting that higher pre- and post-treatment systolic BP (SBP) is associated with an increased risk of symptomatic intracerebral hemorrhage (sICH) and worse outcomes.(1) Furthermore, a similar upper BP threshold (target SBP<180/105mmHg) is recommended for mechanical thrombectomy-eligible patients.(2) Outside of reperfusion therapies, the same guidelines suggest lowering baseline BP by 15% if higher than 220/120 mmHg, with uncertain benefits. Moreover, if below this threshold, the authors state that lowering BP during the first 48-72 hours is not associated with improved mortality or functional outcomes. However, none of the trials supporting this conclusion investigated BP reduction during the first 6 hours after stroke onset.(2) On the other hand, increased BP during the first hours after AIS can be regarded as an adaptative response aimed at enhancing cerebral perfusion. According to the ASA/AHA guidelines on AIS, hypovolemia and arterial hypotension should be corrected to maintain systemic perfusion.(2) A study on 1,278 AIS patients found lower SBP at admission (<140 mmHg) linked to increased 3-month mortality, especially in patients with carotid stenosis.(3) In contrast, another study on 42 patients with > 50% carotid artery stenosis, not undergoing endarterectomy, showed no hemodynamic changes as examined by transcranial doppler at admission and at 3-months follow-up, upon initiating or enhancing antihypertensive treatment. However, an optimal intermediate BP range remains unclear, regardless of eligibility for reperfusion therapies. In the ENCHANTED trial, functional outcome at 90 days did not differ significantly between the intensive BP lowering group (target SBP 130-140 mmHg) versus the guideline group (target SBP<180mmHg) in a population of 2196 IVT-eligible patients, with a mean time to randomization of 3.3 hours and despite a decreased risk of any ICH in the intensive treatment group.(4) More recently, the INTERACT 4 trial investigated whether immediate high BP (>150 mmHg) treatment in patients with suspected AIS administered during ambulance transport (with patients assessed within 2 hours of symptom onset) resulted in better outcomes. The trial randomized 2404 Chinese patients in either an intensive treatment group (target SBP 130-140 mmHg) or usual-care group. Median time from symptom onset until randomization was 1 hour. Stroke was subsequently confirmed in most patients, of whom 53.5% diagnosed with AIS. For patients with AIS, immediate BP-lowering treatment was associated with worse functional outcomes and higher mortality. Conversely, for those with hemorrhagic strokes, BP-lowering led to significantly better functional outcomes, lower mortality, fewer serious adverse events, and reduced hematoma growth.(5) This is consistent with the results of the previous INTERACT 3 trial, aimed at implementing a care bundle protocol (including, BP reduction with a SBP target of <140 mmHg) in patients with acute ICH, which demonstrated improved functional outcomes in the care bundle group versus the usual care group for hemorrhagic stroke.(6) Ensuing from previous studies showing no benefit of intensively lowering BP below a certain threshold in AIS and, and specifically due to the lack of strong evidence supporting BP reduction below 185/110 mmHg in IVT-eligible patients, the results of the Thrombolysis and Uncontrolled Hypertension (TRUTH) study were published.(7) This prospective, observational study conducted across 37 stroke centers in the Netherlands aimed at comparing a BP non-lowering strategy (199 patients) with the usual actively BP lowering strategy (853 patients) in IVT-eligible patients with above guideline-threshold admission BP. The study found no significant benefit in terms of functional outcomes when comparing active BP management to usual care. The adjusted OR for a shift towards a worse 90-day functional outcome was 1.27 (95% CI 0.96–1.68) for active BP reduction compared with no active reduction, despite higher thrombolysis rates and shorter door-to-needle time in the first group. Furthermore, sICH rates were similar.(7) At present, no optimal BP target to achieve best functional outcome in AIS patients has been identified. In addition, the BP threshold for administering IVT has been challenged. Following the progressive expansion of IVT and mechanical thrombectomy indications during the past several years, it seems that admission BP might become less restrictive for reperfusion therapies. Randomized controlled trials would provide important evidence to disprove the adhered benefit of active BP lowering in IVT-eligible patients.

References

1. Berge E, Whiteley W, Audebert H, Marchis GM De, Fonseca AC, Padiglioni C, et al. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J. 2021 Mar 1;6(1):I–LXII.
2. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Vol. 50, Stroke. Lippincott Williams and Wilkins; 2019. p. E344–418.
3. Paciaroni M, Agnelli G, Caso V, Corea F, Ageno W, Alberti A, et al. Effect of carotid stenosis on the prognostic value of admission blood pressure in patients with acute ischemic stroke. Atherosclerosis . 2009;206(2):469–73. Available from: https://www.sciencedirect.com/science/article/pii/S0021915009002470
4. Anderson CS, Huang Y, Lindley RI, Chen X, Arima H, Chen G, et al. Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial. The Lancet . 2019 Mar 2;393(10174):877–88. Available from: https://doi.org/10.1016/S0140-6736(19)30038-8
5. Li G, Lin Y, Yang J, Anderson CS, Chen C, Liu F, et al. Intensive Ambulance-Delivered Blood-Pressure Reduction in Hyperacute Stroke. New England Journal of Medicine . 2024 May 30 ;390(20):1862–72. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa2314741
6. Ma L, Hu X, Song L, Chen X, Ouyang M, Billot L, et al. The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3): an international, stepped wedge cluster randomised controlled trial. The Lancet. 2023 Jul 1;402(10395):27–40.
7. Zonneveld TP, Vermeer SE, van Zwet EW, Groot AED, Algra A, Aerden LAM, et al. Safety and efficacy of active blood-pressure reduction to the recommended thresholds for intravenous thrombolysis in patients with acute ischaemic stroke in the Netherlands (TRUTH): a prospective, observational, cluster-based, parallel-group study. Lancet Neurol . 2024 Aug 1;23(8):807–15. Available from: https://doi.org/10.1016/S1474-4422(24)00177-7