Blood Pressure Target in Acute Stroke to Reduce Hemorrhage After Endovascular Therapy: The Randomized BP TARGET Study Protocol

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Blood Pressure Target in Acute Stroke to Reduce Hemorrhage After Endovascular Therapy: The Randomized BP TARGET Study Protocol

Mikael Mazighi,^1,2,3,4,* Julien Labreuche,⁵ Sebastien Richard,^6,7 Benjamin Gory,^8,9 Bertrand Lapergue,¹⁰ Igor Sibon,¹¹ Jerome Berge,¹² Jean-Marc Olivot,¹³ Peggy Reiner,¹⁴ Emmanuel Houdart,¹⁵ Joseph Broderick,¹⁶ Alain Duhammel,⁵ Benjamin Maier,¹ Amélie Yavchitz,¹⁷ Laurence Salomon,¹⁷ Michael Obadia,¹⁸ Raphael Blanc,^1,2 Julien Savatovsky,¹⁹ and Michel Piotin^1,2

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Abstract

Background: High systolic blood pressure (BP) is associated with an increased risk of intracranial hemorrhage (ICH) in patients undergoing reperfusion therapy. However, there are no data from randomized trials to guide BP management after reperfusion following endovascular therapy (EVT) for patients with acute ischemic stroke (AIS) with large vessel occlusion (LVO). The objective is to evaluate if BP control with a target of 100–129 mmHg systolic BP (“tight” SBP control) can reduce ICH as compared to 130–185 mmHg (“usual” SBP control) in AIS participants after reperfusion by EVT.

Methods: The BP TARGET trial is a multicenter, prospective, randomized, controlled, open-label, blinded endpoint clinical trial. AIS participants with LVO experiencing successful reperfusion are randomly assigned, in a 1:1 ratio, to have a “tight” SBP control (100–129 mmHg) or a conservative SBP control (130–185 mmHg) during the following 24–36 h. The primary outcome is the rate of ICH (either symptomatic or asymptomatic) on follow-up CT scan at 24–36 h. Secondary outcomes include the rate of the symptomatic ICH, the overall distribution of the modified Rankin Scale (mRS) at 90 days, favorable outcome (90–day mRs 0–2), infarct volume at follow-up CT scan at 24–36 h, change in National Institute of Health Stroke Scale at 24 h, and all-cause mortality at 90 days.

Conclusion: This is the first randomized trial directly comparing the efficacy of different SBP targets after EVT reperfusion. This prospective trial aims to determine whether a “tight” SBP control after EVT reperfusion can reduce the risk of ICH.

Keywords: acute ischemic stroke, blood pressure, intracranial hemorrhage, mechanical thrombectomy, randomized controlled trial

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Introduction and Rationale

High blood pressure (BP) in the setting of acute ischemic stroke (AIS), defined by a systolic BP (SBP) >140 mmHg and diastolic BP (DBP) >90 mmHg (1, 2), occurs in up to 50% of patients and is a predictor of unfavorable outcome (3–5). High BP is associated with an increased risk of intracranial hemorrhage (ICH) in AIS patients treated with alteplase (6). In patients eligible for reperfusion therapies, such as alteplase, BP should be below 185/110 mmHg prior to initiation of therapy (7). In the Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST) registry, SBP had a linear relationship with the ICH risk (i.e., the risk increases for high SBP values) (6). High BP values also seem to contribute to the prognosis of AIS patients with large vessel occlusions (LVO) of the anterior circulation treated with endovascular therapy (EVT). Available evidence, in EVT-treated patients, shows that mortality increases for lower and higher baseline SBP values following a U-shaped relationship (8), with a nadir at 157 mmHg (9). In addition, higher SBP peak values independently correlate with unfavorable outcome and a higher ICH rate within 48 h after EVT (8–13). Despite high reperfusion rates and a strong benefit of EVT, more than 50% of patients will remain disabled (14). The lack of clinical recovery may be a consequence, at least in part, of reperfusion injuries including ICH.

Current international guidelines do not discriminate BP management between patients treated with IVT alone and patients treated with EVT and IVT and propose the same BP threshold. Recently, a substantial number of observational studies have begun to shed light on the association between higher post-EVT BP values (SBP >140 or 160 mmHg) and ICH or worse functional outcomes according to the recanalization score (i.e., TICI < 2B vs. TICI ≥ 2B), but with conflicting results (12, 13). Given the lack of data from a randomized controlled trial, an online survey regarding post-EVT BP management was performed across institutions in the United States (StrokeNet Sites)(15). In recanalized patients after EVT, most institutions (36%) seemed to target an SBP in the range of 120–139 mmHg and allow permissive hypertension in nonrecanalized patients.

Taken together, these data underline the need of a randomized controlled trial assessing different BP targets after EVT reperfusion. The BP TARGET trial aims to assess the efficacy of a “tight” BP lowering control (with a target 100–129 mmHg for SBP) versus a more conservative BP control (SBP 130–185 mmHg) following 24 h after reperfusion by EVT in AIS patients.

Outcomes

Primary Outcome

The primary outcome is the rate of subjects with ICH on CT at 24–36 h.

Secondary Outcomes

The secondary clinical efficacy outcomes are the disability assessed by overall mRS distribution at 90 days (shift analysis combining scores of 5 and 6), the 3-month favorable functional outcome at 90 days as defined by a mRS 0–2, the 90-day excellent function outcome as defined by a mRS 0–1, the stroke volume as measured by CT at 24–36 h after EVT; stroke volume at 24–36 h, and the change in NIHSS at 24 h.

Safety outcomes are symptomatic ICH defined by an increase of more than 4 points on the NIHSS, parenchymal hematoma type 2, and all-cause mortality at 90 days.

Feasibility outcome is the rate of patients with mean SBP level during BP management <130 mmHg in the experimental group.