Date: March 21st, 2017

Reference: Qureshi et al. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. NEJM June 2016

Guest Skeptic: Chip Lange is an Emergency Medicine Physician Assistant working primarily in rural Missouri in community hospitals. He has international experience in critical care and emergency medicine. He hosts a blog and podcast called TOTAL EM, which stands for Tools Of the Trade and Academic Learning in Emergency Medicine. Although Chip’s focus is to educate those working in rural and remote settings, his goal has been to help others provide total care everywhere.

Case: A 68 year-old female arrives via EMS for left sided weakness starting two hours prior to arrival in the emergency department. She does not take blood thinners and has lived independently prior to her complaint today. Her head CT without contrast demonstrates a bleed of the right parietal region that measures 52cm3 in size. On arrival her blood pressure is 220/140, which was also found by EMS. The patient’s nurse asks you what blood pressure target you want to aim for given her bleed.

Background: Bleeding in the brain can be bad and can result in morbidity and mortality. There is limited data about the target for systolic blood pressure when treating acute hypertensive response in patients with intracerebral hemorrhage (ICH).

Prior to this study there was the INTERACT-2 trial by Anderson et al that randomized almost three thousand patients with ICH within six hours of symptom onset to either intensive treatment (target systolic blood pressure <140 mm Hg) or control group (target systolic blood pressure <180 mm Hg). Overall, that study found no statistical significance in their primary endpoints of death and disability at 90 days or safety.

There were a number of problems with INTERACT-2 that were discussed on SGEM#73 (How Low Can You Go). One of the main controversies was the secondary ordinal analysis showing a significantly lower modified Rankin Scale (mRS) with intensive treatment OR 0.87 (95% CI 0.77 to 1.00; P = 0.04).

Overall, the evidence for lowing blood pressure in patients with acute ICH is limited.

Clinical Question: In patients with an acute intracerebral hemorrhage, does intensive blood pressure lowering to a systolic blood pressure target of 110-139 mm Hg result in a lower rate of death or disability than a systolic blood pressure target of a 140-179 mm Hg?

Reference: Qureshi et al. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. NEJM June 2016

  • Population: Patients with intracerebral hemorrhage (ICH) that are at least 18 years old with clinical signs consistent with a stroke, GCS of five or greater on arrival, INR <1.5, intraparenchymal hematoma of less than 60cm3 on initial CT scan, and at least one systolic blood pressure reading of 180 mmHg or more between symptom onset and initiation of intravenous antihypertensive treatment.
    • Exclusion Criteria: Systolic blood pressure reduced to <150 mm Hg before randomization or randomization occurred 4.5 hours after symptom onset. Patients with ICH due to previously known neoplasms, AVM, or aneurysms or those with ICH from trauma, ICH located in infratentorial regions such as pons or cerebellum, intraventricular hemorrhage associated with intraparenchymal hemorrhage and blood completely fills one lateral ventricle or more than half of both ventricles, patient to receive immediate surgical evacuation, current pregnancy (or parturition within previous 30 days) or active lactation, use of dabigatran within last 48 hours, platelet count <50,000 mm3, known sensitivity to nicardipine, pre-morbid disability requiring assistance in ambulation or activities of daily living, subject’s living will precludes ICU management, or subject is currently participating in another interventional clinical trial.
  • Intervention: Target systolic blood pressure 110-139 mm Hg (intensive-treatment group). As a note, a patient could have treatment-initiated prior to randomization to lower it below 180 mmHg but would be excluded if systolic pressure was reduced below 140 mm Hg prior to randomization.
  • Comparison: Target systolic blood pressure 140-179 mm Hg (standard-treatment group)
  • Outcome:
    • Primary: Death or disability (modified Rankin Scale 4, 5 or 6) at three months
    • Secondary: Quality of life, hypotension, serious adverse events, hematoma expansion >33% or neurologic deterioration within 24 hours (decrease of two or more points in the GCS score or an increase of four or more points on the NIHSS).

Authors 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.”

checklistQuality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Yes
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. No. This was an open-label trial.
  4. The patients were analyzed in the groups to which they were randomized. Yes. Patients were assessed under intention to treat
  5. The study patients were recruited consecutively (i.e. no selection bias). Unsure based on the information provided
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No. The only person unaware based on the article appears to be the individual reading the head CT.
  8. All groups were treated equally except for the intervention. Yes. They both received the same treatment regimen for blood pressure.
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: 8,532 patients were screened to be included in ATACH-2 with 1,000 patients undergoing randomization. About 60% were male, the average age was about 60 years and the mean systolic blood pressure was 200.6 ± 27.0 mmHg.

No statistical difference in death or disability between groups

  • Primary Outcome: Death or disability defined as a modified Rankin Scale (mRS) was 38.7% (186 of 481) in the intensive-treatment group and in 37.7% (181 of 480) in the standard-treatment group (relative risk, 1.04; 95% confidence interval, 0.85 to 1.27; analysis adjusted for age, initial GCS, and presence or absence of intraventricular hemorrhage).
  • Secondary Outcomes: Treatment related serious adverse events that occurred within 72 hours after randomization was present in 1.6% of patients in the intensive-treatment group and 1.2% in the standard-treatment group. There were significantly more renal adverse events within seven days after randomization in the intensive-treatment group compared to the standard-treatment group (9.0% versus 4.0%, P=0.002).

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  1. Inclusion/Exclusion Criteria: While we do not have a problem with the inclusion criteria, it did change during the middle of the study. Any time a study changes its criteria midway it should be a concern. The logic expressed by the group for this study was that the timeframe for enrolling patients was expanded to 4.5 hours from 3 hours after new data demonstrated that hematoma expansion was equally prevalent whether from 0 to 3 hours or 3 to 4.5 hours. There were also a lot of exclusion criteria, which makes this study less pragmatic. One argument though is that given these patients were most likely the ideal candidates according to the study group and since they still did not meet significant findings this method of management may not be effective. Be careful in drawing such conclusions though as any research has its limitations including only in really applying to the type of patients in that particular study and population (i.e. do not over-generalize).
  2. Lack of Blinding: This was an open-label trial, which can introduce bias into the study. However, the bias would have most likely favoured the intervention. Given that the findings were not significant it actually makes me believe the results even more.
  3. Failure to Reach Blood Pressure Targets: There was a significant amount of failure to achieve target blood pressure within two hours. This was seen in 12.2% of patients in the intensive-treatment group versus 0.8% in the standard-treatment group. Not only could this reduce the treatment effect, but should act as a reminder that it is difficult to drop blood pressures this much in this patient population.
  4. Lack of Power: They did a power calculation based on an event rate of 60% but the observed rate was only 38%. In addition, they stopped the trial early due to futility after a pre-specified interim analysis. This leads to an underpowered study with an increased risk of making a type II error (accepting the null hypothesis that there is no difference when there actually is a difference).
  5. Ordinal Analysis: An ordinal analysis was used in this trial as in other stroke trials. This type of analysis has multiple flaws including the fact that grouping does not make it necessarily a clean cut-off, especially with the subjective points in the mRS and lack of blinding could in turn lead to bias. One of the best examples of an ordinal analysis being spun into something positive is the IST-3 trial that was covered on SGEM#29. We should point out that ATACH-2 used a different cut-off from the INTERACT-2 Trial (mRS 4-6 vs. mRS 3-6). This makes comparing the two studies more challenging.

Comment on authors conclusion compared to SGEM Conclusion: We agree with the conclusion that patients with an acute ICH did not have a lower rate of death or disability with intensive blood pressure lowering compared to the standard blood pressure lowering.

SGEM Bottom Line: Intensive blood pressure reduction (SBP 110-139 mm Hg) does not provide benefit over standard blood pressure reduction (SBP 140-179 mm Hg) in patients with acute intracerebral hemorrhage.

Case Resolution: You discuss with both the nurse and the patient the plan to lower the blood pressure. In your discussion, you review how intensively lowering of the systolic blood pressure beyond 140-179 mm Hg does not appear to be of benefit and could potentially lead to harm such as with the increased risk of renal injury. The healthcare team agrees with this plan and standard lowering of the blood pressure is initiated.

Clinical Application: ATACH-2 fits in with the other limited literature that acute ICH patients do not need to have their blood pressure intensively lowered beyond the standard goal of a systolic blood pressure of 140-179 mm Hg.

Chip Lange

Chip Lange

What do I tell my patient? There is bleeding in your brain and your blood pressure is high. We want to reduce your blood pressure to reduce the risk of further complication. However, there is some research suggesting your blood pressure does not have to be intensively lowered, as it shows little to no benefit and could be harmful. Our goal is to bring that systolic number which is the top number to a range of 140-179 mm Hg.

Keener Kontest: Last weeks’ winner was Linda Dacres, a Nurse Practitioner from Campbellford, Ontario. She knew procalcitonin is the precursor to calcitonin.

Listen to the podcast for this weeks’ keener question. If you know the answer then send an email to TheSGEM@gmail.com with “keener” in the subject line the first person with the correct answer will receive a cool skeptical prize.

FOAM logoOther FOAMed:

  • EMNerd: The Case of the Differing Perspectives
  • REBEL EM: Intensive Blood Pressure Control Doesn’t Benefit Patients with Acute Cerebral Hemorrhage (ATACH-2)
  • The Bottom Line: ATACH-2 Trial
  • CORE EM: Intensive Blood Pressure Lowering in Intracerebral Hemorrhage (ATACH-2 Trial)

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

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