Written by: Jessica Bode, MD (NUEM PGY-3) Edited by: Michael Macias, MD, (NUEM class of 2017) Expert Commentary by: Andrew Naidech, MD, MSPH
Introduction
Hemorrhagic stroke is the second-leading cause of strokes (behind ischemic strokes). The 30-day mortality from intracerebral hemorrhage (ICH) ranges from 35 to 52 percent, with one-half of these deaths occurring within the first two days[1]. A 2010 systematic review estimated that only between 12 and 39 percent of patients go on to achieve independent function[2]. Somewhat intuitively it has long been thought that aggressive blood pressure (BP) control may improve outcomes by limited hemorrhage expansion.
The INTERACT2 study examined the efficacy of intensive systolic blood pressure (SBP) reduction to a goal of <140 mmHg over the course of 1 hour and within a 6 hour window of symptom onset as measured by death and disability. While initially touted as a positive study further examination of the methodology revealed significant differences in the two arms only with ordinal analysis. When comparing this aggressive intervention to the standard treatment SBP goal of <180, the 2013 study found no significant difference between treatment arms. [3]
The 2016 ATACH-2 study sought to reexamine this question: Does aggressively lowering blood pressure lead to decreased death or disability at 90 days?
Study
Qureshi AI et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage (ATACH-2 Trial). NEJM 2016. PMID: 2726234
Study Design
- Randomized, multicenter, two-group, open-label trial (took place in 110 sites in the US, Japan, China, Taiwan, South Korea and Germany)
Population
- Age 18-90
- Intracerebral hemorrhage (< 60 cm3) seen on CT scan with NIHSS score 4 or greater
- GCS ≥5
- Presenting within 4.5 hours of symptom onset (initially within 3 hours but later extended)
- At least one reading of SBP of 180 mmHg or more between symptom onset and the initiation of intravenous antihypertensive treatment
Exclusion Criteria
- 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 day
- 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
Ultimately 8532 patients were screened, 1000 were randomized
Intervention Protocol
Patients were assigned to aggressive (SBP goal <140) or standard (SBP goal <180) arms with BP control achieved via nicardipine or, alternatively, via labetalol or diltiazem. Strict control within these parameters was maintained for 24 hours.
Outcome Measures
Primary
- Modified Rankin scale of 4-6 (death or disability) at 3 months after randomization
Secondary
- European Quality of Life–5 Dimensions (EQ-5D) scores at 3 months
- Visual-analogue scale (VAS) at 3 months
- Proportion of patients with 33% or more expansion in volume of hematoma on 24h delta scan
- Safety outcomes (fall in GCS by 2 or increase of NIH Stroke Score by 4)
- Incidence of serious adverse events within 72 hours
Results
“In conclusion, our results do not support the notion that acute reduction to a target systolic blood pressure of 110 to 139 mmHg in patients with intracerebral hemorrhage is more effective in improving functional outcomes than a reduction to a target systolic blood pressure of 140 to 179 mm Hg.”
Aggressive SBP reduction to a target of 110-139 mmHg did not result in lower rate of death or disability compared to the standard treatment goal of 140-179 mmHg. There was no difference between groups in mRS of 4-6 at 3 months (38.7% in intervention arm, 37.7% in control arm).
Interpretation
Strengths
- Multi-centered trial
- Clinically meaningful outcomes
Weaknesses
- During the trial, ATACH-2 expanded enrollment from patients who presented within 3 hours to those who presented within 4.5 hours. As the authors acknowledge in the paper, this could mask a time-dependent loss of benefit but they deem this unlikely as subgroup analyses of INTERACT2 data did not demonstrate this phenomenon.
- Intracerebral hemorrhage grouped as a single entity
- 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. It’s difficult to interpret its impact on treatment effect.
- 56.2% of patients were Asian making it difficult to generalize to primarily European populations though when subgroups extracted out again no clinically significant benefit to aggressive therapy was found.
The Bottom Line
As mentioned above, ATACH-2 serves as a rebuttal to the purported positive results of the INTERACT2 trial. On further analysis, the interpretation of INTERACT2 results was somewhat flawed and many experts have ultimately come to view it as a negative trial, consistent with ATACH-2. Dr. Rory Spiegel discusses this in more depth here.
As it stands, decisions should be made in conjunction with neurology and neurosurgery at your institution, but the literature at present does not support aggressive BP control and in fact this practice may lead to harm in the form of decreased cerebral perfusion. Standard SBP target of <180 mmHg should probably be maintained.
Expert Commentary
Intracerebral hemorrhage (ICH) is the most deadly form of stroke and has no FDA approved treatment . This is not to say nothing can be done, and the lack of specific therapies has heightened the importance of optimizing the management. Protocols to improve diagnosis, obtain appropriate imaging, obtain subspecialty care, screen for dysphagia, ensure rehabilitation assessments and accredit Stroke Centers are important. Within these broad strokes, hypotheses about which specific management strategies are likely to improve biomarkers and, subsequently, patient outcomes, can be rigorously tested.
Severe hypertension is both a risk factor and a cause of ICH. Hypertension is plausibly linked to growth of the hematoma, a proximate cause of worse patient outcomes. Thus, it is reasonable to test the hypothesis that lowering blood pressure reduces hematoma growth and, subsequently, improves patient outcomes.
INTERACT2 was negative for its primary endpoint of improved odds of good outcome with a dichotomous ordinal scale, while statistically significant for ordinal regression (a method to determine if there is a shift along the score) and health-related quality of life (HRQoL). ATACH-2 found no evidence of overall benefit to rapid blood pressure lowering, and an increased rate of renal failure. There was no evidence that rapid lowering of blood pressure reduced hematoma growth, which makes the potential mechanism of improved outcomes conjectural.
These studies highlight another problem: Outcomes assessment in clinical trials may be too crude to show meaningful differences between groups. Since INTERACT2 and ATACH-2 were designed, NIH has created, normed, and distributed new benchmarks for HRQoL, the Patient Reported Outcomes Measurement Information System (PROMIS) and Neuro-QOL. We have previously validated PROMIS and Neuro-QOL against ordinal scales, and found they highlight facets of HRQoL that are important, but not as well measured by ordinal scales while being more statistically powerful [4]. They are now generally accepted as pivotal outcomes for clinical research [5].
Aggressive blood pressure lowering is likely to be of some benefit; a target of 140 – 160 mm Hg systolic is reasonable for patients with systolic blood pressure <220 mm Hg pending the next update of evidence based guidelines. Going forward, accurate assessment of patient outcomes with sensitive, powerful scales will make clinical trials more meaningful, and more likely to be positive.
Andrew Naidech, MD, MSPH
Professor of Neurology (Stroke and Neurocritical Care), Anesthesiology, Medical School Sciences, Neurological Surgery, and Preventive Medicine (Health and Biomedical Informatics), Northwestern University
References
- Flaherty ML, Haverbusch M, Sekar P, et al. Long-term mortality after intracerebral hemorrhage. Neurology 2006; 66:1182.
- van Asch CJ, Luitse MJ, Rinkel GJ, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 2010; 9:167.
- Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013; 368:2355.
- Naidech AM, Beaumont JL, Berman M, Francis B, Liotta E, Maas MB, Prabhakaran S, Holl J, Cella D.Dichotomous "Good Outcome" Indicates Mobility More Than Cognitive or Social Quality of Life. Crit Care Med. 2015 Aug;43(8):1654-9. doi: 10.1097/CCM.000000000000108
- Salinas J, Sprinkhuizen SM, Ackerson T, Bernhardt J, Davie C, George MG, Gething S, Kelly AG, Lindsay P, Liu L, Martins SC, Morgan L, Norrving B, Ribbers GM, Silver FL, Smith EE, Williams LS, Schwamm LH.An International Standard Set of Patient-Centered Outcome Measures After Stroke. Stroke. 2016 Jan;47(1):180-6. doi: 10.1161/STROKEAHA.115.010898. Epub 2015 Nov 24.