Background

Hemorrhagic stroke accounts for only 11-22% of all strokes but up to 50% of all stroke mortality. Additionally, there is significant disability associated with the disease in survivors. Much of our attention in the Emergency Department is guided towards preventing expansion of bleeding and secondary injury after the initial insult. Physiologically, controlling blood pressure has always appeared to be a reasonable goal as it may decrease hematoma expansion and thus mortality. However, there is little high-quality evidence to guide clinicians in determining what the goal blood pressure should be and whether there’s truly a patient centered benefit to aggressive blood pressure management. The recently published INTERACT-2 trial demonstrated no benefit for death or disability for aggressive blood pressure control when started within 6 hours of symptom onset (though the authors touted benefits seen only after ordinal analysis) but some critics have argued that treatment should be started earlier.

Clinical Question

Does aggressively lowering blood pressure (target SBP < 140 mm Hg) lead to decreased death or disability at 90 days?

Population

Patients > 18 years with intracerebral hemorrhage (< 60 cm3) and a GCS > 5 who presented within 4.5 hours of symptom onset and at least one blood pressure reading with an SBP > 180 mm Hg

Intervention

Aggressively lowering blood pressure to an SBP = 110-139 mm Hg for 24 hours using nicardipine (1st line) and labetalol, diltiazem or urapidil (2nd line)

Control

Standard treatment guided at an SBP = 140 - 179 mm Hg for 24 hours using nicardipine (1st line) and labetalol, diltiazem or urapidil (2nd line)

Outcomes

Primary: Death or disability (Modified Rankin Scale (mRS) 4-6) at 90 days
Secondary: EQ-5D utility index score at 3 months, > 33% expansion of hematoma at 24 hours

Design

Randomized, multicenter (110 sites), multinational (6 countries), open-label trial. Study powered to detect 10% difference between groups

Excluded

Time of symptom onset could not be reliably assessed
Admission SBP >240mmHg on two repeat measurements at least 5 min apart
Previously known neoplasms, AVM, or aneurysms
Intracerbral hematoma considered to be related to trauma
ICH located in intratentorial regions such as pons or cerebellum
Intraventricular hemorrhage associated with intraparenchymal hemorrhage and blood completely fills on lateral ventricle or more than half of both ventricles
Patient is considered a candidate for immediate surgical intervention by neurosurgery
Pregnancy, lactation, or parturition within previous 30d
Any history of bleeding diathesis or coagulopathy
Use of warfarin within the last 5d
Platelet count < 50,000/mm3 Known sensitivity to nicardipine Pre-morbid mRS of 4 or greater Patient with living will that precludes aggressive ICU management Signed and dated informed consent by patient, representative or surrogate could not be obtaine

Primary Results

  • > 8500 patients screened and 1000 patients recruited for inclusion in the study (initial goal was for 1280 patients)
  • Mean SBP on presentation 200.6 +/- 27.0 mm Hg
  • Baseline characteristics similar between the two groups

Critical Findings

Primary outcome (death or disability (mRS 4-6))

  • Standard treatment: 37.7% (181/480)
  • Intensive treatment: 38.7% (186/481)
  • Relative Risk: 1.02 (95% CI 0.83 – 1.25)
  • No statistically significant difference between groups
  • Study was stopped early due to futility (i.e.extremely low likelihood of finding the proposed treatment benefit) for the primary outcome

Secondary measures

  • Mortality
  • No statistically significant difference in EQ-5D measures or hematoma expansion between groups
  • No significant difference in death at 3 months or neurologic deterioration in 24 hours
  • Higher rate of all serious adverse events at 90 days in intensive-treatment group
  • Renal adverse events increased in intensive-treatment group: 9.0% vs. 4.0%

Strengths

  • Large study that was appropriately randomized and asked a clinically relevant question
  • Multicenter, multinational nature of study increases generalizability
  • Outcome assessment performed by investigators blinded to treatment arm
  • Follow up was near complete for the primary outcome (96.1%)

Limitations

  • The study initially sought to enroll patients < 3 hours after symptom onset but changed to < 4.5 hours. The authors state that this change was made due to new data suggesting that the occurrence of hematoma expansion was equally prevalent among patients presenting < 3 hours and who presented 3-4.5 hours but this explanation is unsatisfying.
  • Study was open-label introducing significant biases for clinicians but these biases are likely to favor the intensive-treatment group
  • Extensive exclusion criteria
  • Primary treatment failure (inability to achieve target BP within 2 hours) was seen in 12.2% of patients in the intensive-treatment group vs just 0.8% in the standard-treatment group. This may have reduced the treatment effect but it also reflects the difficulty in aggressively dropping blood pressure in these patients

Author's Conclusions

“The treatment of participants with intracerebral hemorrhage to achieve a target systolic
blood pressure of 110 to 139 mm Hg did not result in a lower rate of death or disability than standard reduction to a target of 140 to 179 mm Hg.”

Our Conclusions

Intensive blood pressure control (SBP 110-139 mm Hg) in patients with intracerebral hemorrhage does not improve 90 day death or disability (mRS 4-6) in comparison to standard management.

Potential Impact To Current Practice

This study confirms the negative findings seen in the INTERACT-2 trial that aggressive control of blood pressure in patients with intracerebral hemorrhage does not improve outcomes. Based on current evidence, intensive blood pressure reduction should not be pursued.

Bottom Line

There does not appear to be a benefit to aggressive blood pressure reduction in patients with intracerebral hemorrhage. Standard therapy aimed at SBP < 180 mm Hg should be pursued in most patients.

Read More

EM Nerd: The Case of the Differing Perspectives

References

Anderson CS et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. NEJM 2013; 368(25): 2355-65. PMID: 23713578

Qureshi AI et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage (ATACH-2 Trial). NEJM 2016. PMID: 27276234