New England Journal of Medicine SEPTEMBER 15, 2016

Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage

Adnan I. Qureshi, Yuko Y. Palesch, William G. Barsan, et al. for the ATACH-2 Trial Investigators

Bottom Line

The ATACH-2 trial demonstrated that early intensive systolic blood pressure lowering (target 110-139 mmHg) did not result in a significant improvement in the rate of death or disability at 3 months compared to standard care (target 140-179 mmHg) in patients with acute intracerebral hemorrhage.

Key Findings

1. The primary outcome of death or disability (modified Rankin scale score 4-6) at 3 months occurred in 38.7% of patients in the intensive-treatment group versus 37.7% in the standard-treatment group (adjusted relative risk 1.04; 95% CI, 0.85 to 1.27; P=0.72).

2. Intensive treatment did not significantly reduce hematoma expansion or improve neurological outcomes.

3. There was a significantly higher incidence of renal adverse events within 7 days in the intensive-treatment group (9.0% vs. 4.0%; P=0.002).

4. The trial was stopped early for futility based on the results of the second interim analysis.

Study Design

Design

RCT

Open-Label

Sample

1,000

Patients

Duration

3 mo

Median

Setting

Multicenter, international

Population Adults with spontaneous supratentorial intracerebral hemorrhage, hematoma volume <60 cm3, GCS ≥5, presenting within 4.5 hours of onset with systolic blood pressure ≥180 mmHg.

Intervention Intensive blood pressure lowering with intravenous nicardipine to a target of 110-139 mmHg, initiated within 4.5 hours of symptom onset and maintained for 24 hours.

Comparator Standard blood pressure lowering with intravenous nicardipine to a target of 140-179 mmHg, initiated within 4.5 hours of symptom onset and maintained for 24 hours.

Outcome Death or disability at 3 months, defined as a score of 4 to 6 on the modified Rankin scale.

Study Limitations

• The trial was stopped early for futility, which may have limited the power to detect smaller, yet potentially clinically relevant, treatment effects.

• The trial was open-label, which introduces potential bias in clinical management and outcome assessment despite central blinded adjudication.

• The study population was heavily weighted toward patients from Asian centers (56%), which may affect the generalizability of results to other populations.

• The target blood pressure levels were lower than those achieved in previous studies like INTERACT-2, making comparisons between trials complex.

Clinical Significance

The findings challenge the hypothesis that more aggressive, early systolic blood pressure lowering provides additional benefit over standard goals for acute intracerebral hemorrhage and suggests it may increase the risk of adverse events, particularly renal impairment.

Historical Context

Following the modest potential benefits suggested by the INTERACT-2 trial for intensive BP lowering in ICH, the ATACH-2 trial was designed to rigorously test whether a more aggressive, ultra-early intensive strategy could further improve functional outcomes in a larger, multi-center, Phase III setting.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the physiological rationale for targeting early systolic blood pressure lowering in patients with acute intracerebral hemorrhage (ICH), and why was the 110–139 mmHg range specifically chosen as the 'intensive' target in ATACH-2?

Key Response

The primary goal is to minimize hematoma expansion, which is the most significant predictor of early neurological deterioration. The target of 110–139 mmHg was chosen to test whether lower-than-standard targets (previously 140–180 mmHg) could further limit bleeding without causing cerebral ischemia, a concern known as the 'ischemic penumbra' theory in ICH which recent studies suggest is less of a risk than previously thought.

Resident

The ATACH-2 trial reported an increased incidence of renal adverse events in the intensive-treatment group. How should this finding influence your choice of antihypertensive agent and monitoring parameters when managing a patient with hyperacute ICH?

Key Response

ATACH-2 found that intensive BP lowering (target 110-139 mmHg) led to significantly higher rates of acute kidney injury (9% vs 4%). In practice, this means clinicians should prioritize agents with predictable titration (like nicardipine or clevidipine), avoid 'overshooting' below 110 mmHg, and closely monitor serum creatinine and urine output during the first 72 hours of intensive therapy.

Fellow

When comparing ATACH-2 to the INTERACT-2 trial, what differences in study design, particularly regarding the timing of intervention and the specific blood pressure targets achieved, might explain the discrepancy in their primary outcome findings?

Key Response

INTERACT-2 showed a borderline benefit for intensive lowering (target <140) in functional outcomes (mRS shift), while ATACH-2 (target 110-139) was neutral. A key difference is that ATACH-2 achieved the target BP much faster (within ~30 mins) using IV nicardipine, compared to the more gradual lowering in INTERACT-2. The 'ultra-intensive' target and the speed of reduction in ATACH-2 may have crossed a threshold where systemic risks (like renal failure) outweighed the benefit of preventing hematoma expansion.

Attending

Given the results of ATACH-2, how do you reconcile the pressure to 'do something' to prevent hematoma expansion with the evidence that intensive BP lowering does not improve 3-month disability? How do you teach this nuance to trainees?

Key Response

The teaching point is that the 'sweet spot' for BP in ICH is likely 140 mmHg, not lower. ATACH-2 provides high-level evidence that driving SBP below 140 mmHg into the 110-130 range provides no additional neuroprotection but increases systemic morbidity. I teach that we should be aggressive in reaching <140 mmHg but equally aggressive in preventing hypotension or 'over-treatment' that compromises renal perfusion.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

ATACH-2 was terminated early for futility after a planned interim analysis of 1,000 patients. From a statistical and trial design perspective, what are the potential risks of early termination for futility, and how might this have affected the precision of the safety signals observed in the trial?

Key Response

Early termination for futility can lead to an underestimation of smaller, potentially significant treatment effects that might have emerged with a larger sample size (Type II error). However, for safety, the early termination in ATACH-2 actually strengthened the renal safety signal; because a significant difference in AKI was already apparent at the interim point, it suggested a very high effect size for treatment-related harm.

Journal Editor

As a reviewer, how would you evaluate the 'control group' management in ATACH-2, and did the high-quality care received by the standard-treatment group potentially dilute the experimental arm's effect size?

Key Response

A common threat to validity in BP trials is 'protocol creep' or high-performance bias in the control group. In ATACH-2, the control group (target 140-179) actually achieved a mean SBP of ~141 mmHg within hours. Because the control group was treated so efficiently near the lower end of their target, the actual physiological difference between 'intensive' and 'standard' care was narrower than planned, making it difficult for the intervention to demonstrate superiority.

Guideline Committee

The 2022 AHA/ASA Guidelines for ICH management downgraded the recommendation for intensive BP lowering. Based on ATACH-2, what specific language should be included regarding the lower-bound safety limit for systolic blood pressure in the hyperacute phase?

Key Response

Following ATACH-2, guidelines (such as the 2022 AHA/ASA update) moved toward recommending a target SBP of 140 mmHg but specifically cautioned against targets below 110 mmHg. The rationale should emphasize that while achieving <140 mmHg is 'safe' (Class 1, LOE A), the specific 'intensive' target of <130 mmHg is now considered to have no clear benefit and carries a 'Class 3: Harm' signal for renal dysfunction.

Clinical Landscape

Noteworthy Related Trials

2010

ITCH Trial

n = 131 · Lancet Neurology

Tested

Intensive blood pressure reduction (target SBP <140 mmHg)

Population

Patients with acute spontaneous intracerebral hemorrhage

Comparator

Standard care (target SBP <180 mmHg)

Endpoint

Feasibility, safety, and hematoma growth

Key result: The study demonstrated that intensive blood pressure reduction was feasible and safe without increasing neurological deterioration.

2013

INTERACT2 Trial

n = 2,839 · NEJM

Tested

Intensive blood pressure lowering (target SBP <140 mmHg)

Population

Patients with spontaneous intracerebral hemorrhage

Comparator

Guideline-recommended standard care (target SBP <180 mmHg)

Endpoint

Death or major disability at 90 days

Key result: Intensive blood pressure lowering did not significantly reduce the primary endpoint of death or major disability compared to standard care, though a trend favored intensive control.

2019

ADAPT Trial

n = 260 · JAMA Neurology

Tested

Intensive blood pressure control (target SBP 110–139 mmHg)

Population

Patients with acute spontaneous intracerebral hemorrhage within 6 hours of onset

Comparator

Standard care (target SBP 140–179 mmHg)

Endpoint

Perihematomal edema expansion

Key result: Intensive BP lowering was associated with reduced perihematomal edema expansion compared to standard care.

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