Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage

Qureshi et al. NEJM 2016 DOI: 10.1056/NEJMoa1603460

Clinical Question

• In patients with acute intracerebral haemorrhage and who are hypertensive, does rapid lowering of systolic blood pressure compared to standard therapy improve patient outcomes ?

Design

• Randomised, multi-centre, open-label
• Central randomisation using trial website by minimisation algorithm combined with biased-coin method
• Follow up period of 3 months
• Power calculation based on assumption that death or disability would be 10% lower in intervention group. Expected control event rate of 60%.
  • alpha error 0.05, power 90%
  • Sample size of 1280 required taking into account non-adherence
• Intention-to-treat analysis

Setting

• 110 sites in United States, Japan, China, Taiwan, South Korea and Germany
• May 2011 to September 2015

Population

• Inclusion:
  • 18 years and above
  • GCS > 4
  • Intraparenchymal haematoma of less than 60cm3 on initial CT scan
  • Within 3 hours (extended to 4.5 hours) of symptom onset

  • At least one reading of systolic blood pressure of 180 mmHg or more between symptom onset and the initiation of intravenous antihypertensive treatment

• Exclusion:
  • Time of symptom onset not reliably established
  • Previously known AVM, neoplasm or aneurysm
  • Intracerebral hematoma considered to be related to trauma.
  • lCH located in infratentorial regions such as pons or cerebellum
  • IVH associated with intraparenchymal hemorrhage and blood completely fills one lateral ventricle or more than half of both ventricles
  • Subject is considered a candidate for immediate surgical intervention by the neurosurgery service
  • Pregnancy or parturition within previous 30 days or active lactation
  • Any history of bleeding diathesis or coagulopathy
  • Use of warfarin within the last 5 days
  • A platelet count less than 50,000/mm3
  • Known sensitivity to nicardipine
  • Pre-morbid mRS of 4 or greater
  • Subject’s living will precludes aggressive ICU management
• 8532 patients screened, 1000 randomised

Intervention

• * Treatment could be initiated before randomisation to lower the systolic blood pressure to less than 180 mmHg but were excluded if systolic BP reduced below 140 mmHg before randomisation

• Target systolic BP 110 to 139 mmHg throughout the 24 hours after randomisation

Control

• Target systolic BP 140 to 179 mmHg throughout the 24 hours after randomisation

Management common to both groups

• 1st line = IV nicardipine infusion
  • initiated at 5mg/hr, increased by 2.5mg/hour every 15 minutes as needed, up to a maximum dose of 15mg/hr
• 2nd line (if target not achieved after 30 mins) = IV labetalol (IV diltiazem or urapidil if labetolol not available)

Outcome

• Primary outcome:
  • Proportion of patients who had modified Rankin scores 4 to 6 at 3 months (significant disability or death)
    • No difference between groups (38.7% in intervention, 37.7% in control)
      • Unadjusted analysis: relative risk 1.02 (CI 0.83 – 1.25, p=0.84)
      • Adjusted analysis: relative risk 1.04 (CI 0.85 – 1.27, p=0.72)
• Secondary outcome:
  • Unadjusted analysis showed no difference between groups in:
    • EQ-5D scores at 3 months
    • VAS at 3 months
    • Proportion of patients with expansion of 33% or more in volume of haematoma on 24 hour scan compared to baseline scan
    • Safety outcomes (fall in GCS by 2 or increase of NIH Stroke Score by 4)
    • Incidence of serious adverse events within 72 hours
  • Higher incidence of serious adverse events within 3 months in intervention group when analysis adjusted
    • 25.6% in intervention, 20% in control; p=0.05

 

• Primary treatment failure = not achieving target within 2 hours after randomisation
  • 61 (12.2%) in intervention arm, 4 (0.8%) in control arm; p<0.001
• Secondary treatment failure = hourly minimum systolic BP above target range for 2 consecutive hours during the period of 2 to 24 hours after randomisation
  • 78 (15.6%) in intervention arm, 7 (1.4%) in control arm; p<0.001

Authors’ Conclusions

• The results of the trial do not support the reduction of systolic blood pressure to a target of 110 to 139 mmHg in patients with intracerebral haemorrhage

Strengths

• Multi-centre trial
• Clinically meaningful and relevant outcome measures

Weaknesses

• Recruitment criteria changed during the trial
• Reasons for failure to randomise screened population not included
• Under-powered – power calculations based on event rate of 60%, actual observed event rate in study of 38%, increasing likelihood ot type 2 error
• More than 50% of patients recruited from Asia sites and may not be reflective of European population
• Intracerebral haemorrhage grouped as a single entity
• Significant difference between groups with regards to treatment failure (primary and secondary)

The Bottom Line

• The results of this trial and that of the INTERACT2 trial do not support an early, intensive control of systolic blood pressure in patients with acute intracranial haemorrhage

External Links

• [article] Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage
• [further reading] Supplementary material
• [further reading] Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage (INTERACT2)

Metadata

Summary author: Adrian Wong
Summary date: 15 July 2016
Peer-review editor: Duncan Chambler