MAPAS

Early Manipulation of Arterial Blood Pressure in Acute Ischemic Stroke(MAPAS):Results of a Randomized Controlled Trial

Luiz Antonio Nasi. Neurocritical Care 2019; doi: https://doi.org/10.1007/s12028-018-0642-5

Clinical Question

  • In adult patients presenting within 12 hours of an acute ischaemic stroke (AIS), which of three targeted and pre-specified systolic blood pressure (SBP) ranges results in an improved functional outcome at 90 days?

Background

  • Significant hypo- and hypertension is associated with poorer outcomes following AIS, following a U-shaped distribution for functional recovery
  • Hypotension may lead to under perfusion of the injured brain, wheras hypertension may increase the risk of haemorrhagic transformation
  • Most guidelines recommend a SBP between 140mmHg and 220mmHg in the acute phase
  • The American Stroke Association guidelines state that the benefits of initiating hypertension treatment in the first 48-72 hours are uncertain, although a decrease of 15% in the initial SBP might be reasonable
  • The CATIS study was a large Chinese study published in JAMA in 2014, showing no improvement in functional outcomes with SBP lower in the first 24 hours following cerebrovascular accident (CVA)
  • The recently published RIGHT2 study assessed the use of pre-hospital nitrates to lower pre-hospital blood pressure following suspected CVA but showed no difference in functional outcomes
  • The optimal target for SBP following acute stroke is therefore unclear at present
  • This study aimed to answer that question by investigating functional outcomes for three SBP targets in acute stroke patients not receiving thrombolysis

Design

  • A randomised, single centre controlled trial
  • Computer generated random sequence
  • Open label study
  • Outcome assessment blinded
  • The primary endpoint was ‘good outcome’, defined as modified Rankin Score (mRS) 0–2 at 90-days
  • Sample size of 75 patients per group (total of 225 patients) would provide 80% power to reject the null hypothesis of no difference between treatment groups for a good outcome on mRS
  • Analysis on modified intention to treat principle (5.6% of randomized patients excluded due to final diagnosis being non-stroke after subsequent investigations
  • Differences examined among three randomised groups and between manipulated or non-manipulated SBP

Setting

  • A public university hospital in southern Brazil
  • December 2009 to December 2013

Population

  • Inclusion: Adult patients ≥ 18 years of age with AIS, presenting within 12 hours of symptom onset and unsuitable for IV thrombolysis according to current guidelines
  • Exclusion: Poor life expectancy, pregnancy, acute heart failure, acute coronary event in the previous 3 months, previous intracranial hemorrhage, previous ischemic stroke with a premorbid mRS > 1, history of bleeding diathesis or coagulopathy (including warfarin use), thrombocytopenia (< 100,000/mm3 ), major surgery within the previous 6 weeks, and renal failure on renal dialysis.
  • 1033 AIS patients screened; 36% excluded for receiving thrombolysis; 23% excluded as pre-stroke mRS was > 1; 8% excluded for acute heart failure and 10.7% for other reasons.
  • 231 patients randomized, 77 patients to each of the three SBP target groups
    • Comparing baseline characteristics between Group 1 (target 140-160mmHg) vs. Group 2 (target 161-180mmHg) vs. Group 3 (target 181-200)
      • Patients excluded post randomization due to stroke mimic
        • Significantly higher in Group 3: 0 vs. 2 vs. 11
      • Blood glucose
        • Significantly lower in Group 3: 149 vs. 156 vs. 128
      • No significant difference in:
        • Age: 68 vs. 69. vs. 67
        • Prior stroke/TIA: 31% vs. 25% vs. 23%
        • Systolic BP at admission: 166 vs. 163 vs. 169
        • NIHSS score: 7 vs. 8 vs. 8
        • Stroke location
          • Anterior circulation: 94% vs. 89% vs. 85%
        • Hypodensity >1/3rd MCA territory: 29% vs. 28% vs. 24%

Intervention

  • Three intervention arms, aiming for a systolic blood pressure target for 24 hours following study enrolment of either:
    1. 140-160mmHg (median BP achieved: 153mmHg)
    2. 161-180mmHg (median BP achieved: 163mmHg)
    3. 181-200mmHg (median BP achieved: 178mmHg)

Control

  • No control groups

Management common to both groups

  • The SBP was maintained according to the randomised target during the first 24 hours using one of following strategies:
    • SBP in the target range: no specific intervention to manipulate BP
    • SBP lower than the target range: intravenous (IV) 500–1000 ml bolus of 0.9% saline solution and if necessary followed by IV norepinephrine
    • SBP higher than the target range: IV esmolol followed by nitroprusside, if necessary, to lower SBP to target level
  • Patients received the standard management for non-thrombolised AIS, including statins, antiplatelet agents (Aspirin or Clopidogrel) and enoxaparin for deep venous thrombosis prevention immediately after the first CT scan
  • The patients with cardioembolic strokes received anticoagulation for secondary prevention as soon as possible depending on the stroke size

Outcome

  • Primary outcome: No significant difference in a ‘good outcome’ (mRS score 0-2 at 90 days) between the systolic blood pressure groups
    • Group 1 vs. Group 2 vs. Group 3
      • 51% vs. 52% vs. 39%, p=0.27
  • The mean time from symptom onset to reach the allocated SBP target was in total 7h 6 min: 5 h from symptom onset to randomisation and 2h 6 min from the randomisation to reach the SBP stratus.
  • SBP was manipulated in 176 patients (76.2%). 90 patients (39%) had their SBP increased and 86 patients (37.2%) had their SBP decreased
  • Secondary outcomes:
    • Significantly higher incidence of symptomatic intracranial haemorrhage in the highest systolic blood pressure group
      • 1% vs. 3% vs. 9%, p=0.049
    • No difference in mortality between the three groups
      • 14% vs. 19% vs. 11%, p=0.4
    • Ordinal analysis of the distribution of mRS scores in the three groups showed no difference (p=0.51)
    • Logistic regression analysis adjusting for age, blood glucose, baseline NIHSS score, hypodensity >1/3rd MCA territory, TOAST classification and BP manipulation – probability of a good outcome at 90 days was significantly greater for Group 2 vs. Group 3, p=0.03
      • mRS 0-2: 51% vs. 52%, vs. 39%
    • The greatest probability of a good outcome was in patients who received no SBP manipulation when compared with SBP manipulated patients (62% vs. 44%; p=0.04)
    • All adverse effects were felt to be associated with noradrenaline use, with 1.3% and 6.0% of patients in groups 2 and 3 having acute coronary syndromes

Authors’ Conclusions

  • The results of the MAPAS trial suggests that the neurological functional outcome assessed by the mRS at 90 days was not significantly different among the three pre-specified SBP groups
  • No patient had acute neurological deterioration related to the BP reduction in 24 hours
  • Spontaneous intracranial haemorrhage occurred more frequently in patients with higher SBP (181–200 mmHg)
  • After adjusting for confounders, the chance of good outcome in 90 days was greater in patients in which SBP was maintained in the 161–180 mmHg range in the first 24 hours after stroke

Strengths

  • Patient-centred outcome
  • Outcome assessors blinded to study group
  • Haemorrhagic stroke transformation analysed in subgroup analysis
  • Target BP reached at a mean time of 2 hours and 6 minutes following randomisation
  • Power calculation performed based on the functional independence expected following a thrombolysed stroke

Weaknesses

  • Single-centre study limits generalisability
  • Small sample size despite four years of recruitment
  • Wide exclusion criteria used
  • No invasive BP monitoring used and SBP measured only every 60 minutes following the first hour
  • Poor between-group separation, other than between the lowest and highest groups. A better design may have been 140-160mmHg vs. 180-200mmHg
  • Target SBP not sustained over 24 hours in around 40% of group 2 and 3 patients
  • 16% of patients had no functional deficit at baseline. Manipulation of blood pressure was unlikely to change functional outcome in this group
  • 30% of patients were excluded from thrombolysis as hypodensity on CT was too pronounced
  • Open label study design meant that physician bias may have influenced patient management
  • Adjusted analysis on small numbers of patients unlikely to be meaningful data
  • The power of the study may have meant that clinically significant differences may not have been detected i.e. there was a difference of 13% between the primary outcome rate in group 2 and group 3. This difference if real, would still be clinically significant
  • Patients excluded post randomisation

The Bottom Line

  • This study will not change my current practice of not manipulating the systolic blood pressure following acute ischaemic stroke, unless it is unacceptably low (< 120mmHg) or high (>200mmHg)
  • The results of this paper are not applicable to stroke patients who have received thrombolysis or mechanical clot retrieval therapy or who are anticoagulated
  • I await future studies that use the presence or absence of ischaemic penumbra on CT perfusion imaging to guide SBP targets

External Links

Metadata

Summary author: Fraser Magee @fraz65
Summary date: 10/05/2019
Peer-review editor: David Slessor

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