Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II: Design, Methods, and Rationale

Abstract

The December 2003 report from the National Institute of Neurological Disorders and Stroke (NINDS) Workshop on priorities for clinical research in intracerebral hemorrhage (ICH) recommended clinical trials for evaluation of blood pressure management in acute ICH as a leading priority. The Special Writing Group of the Stroke Council of the American Heart Association in 1999 and 2007 emphasized the need for clinical trials to ensure evidence-based treatment of acute hypertensive response in ICH. To address important gaps in knowledge, we conducted a pilot study funded by the NINDS, Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) I Trial, during 2004–2008 to determine the appropriate level of systolic blood pressure (SBP) reduction. We now have initiated a multicenter, randomized Phase III trial, the ATACH II Trial, to definitively determine the efficacy of early, intensive, anti-hypertensive treatment using intravenous (IV) nicardipine initiated within 3 h of onset of ICH and continued for the next 24 h in subjects with spontaneous supratentorial ICH. The primary hypothesis of this large (N = 1,280), streamlined, and focused trial is that SBP reduction to ≤140 mm Hg reduces the likelihood of death or disability at 3 months after ICH, defined by modified Rankin scale score of 4–6, by at least 10% absolute compared to standard SBP reduction to ≤180 mm Hg. The ATACH II trial is a natural extension of numerous case series, the subsequent ATACH I pilot trial, and a preliminary, randomized, and controlled trial in this patient population funded by the Australian National Health and Medical Research Council. Both trials recently confirmed the safety and tolerability of both the regimen and goals of antihypertensive treatment in acutely hypertensive patients with ICH, as proposed in the present trial. The underlying mechanism for this expected beneficial effect of intensive treatment is presumably mediated through reduction of the rate and magnitude of hematoma expansion observed in approximately 73% of the patients with acute ICH. The Australian trial provided preliminary evidence of attenuation of hematoma expansion with intensive SBP reduction. The ATACH II trial will have important public health implications by providing evidence of, or lack thereof, regarding the efficacy and safety of acute antihypertensive treatment in subjects with ICH. This treatment represents a strategy that can be made widely available without the need for specialized equipment and personnel, and therefore, can make a major impact upon clinical practice for treating patients with ICH.

Intensive blood-pressure lowering in patients with acute cerebral hemorrhage

“…The observed rate of death or disability at 3 months in the standard-treatment group (37.7%) was lower than the rate that was anticipated in the trial design on the basis of previous literature (60%). 6,19,20 A high percentage of patients with favorable characteristics at baseline (e.g., 56% of the patients had a baseline GCS score of 15) may have conferred a predisposition to a favorable outcome in our trial sample regardless of treatment (ceiling effect), making it difficult to discern the beneficial effect of an intensive reduction in the systolic blood-pressure level in this trial. 6 The high proportion of favorable outcomes may also have resulted from the monitoring and standardizing intensity of medical care provided at each site and a low rate of withdrawal of care among participants recruited in the trial (as compared with a 34% rate outside clinical trials).…”

“…At least one reading of systolic blood pressure of 180 mm Hg or more between symptom onset and the initiation of intravenous antihypertensive treatment was required for eligibility. 6 Treatment could be initiated before randomization to lower the systolic blood pressure to less than 180 mm Hg, which is consistent with guidelines from the American Stroke Association Stroke Council, 12 but patients were not eligible if the systolic blood pressure was reduced to less than 140 mm Hg before randomization. The initiation of intravenous antihypertensive treatment according to the trial protocol (available with the full text of this article at NEJM.org) and randomization had to occur within 4.5 hours after symptom onset.…”

“…The rate of death or disability among patients randomly assigned to intensive reduction in the systolic bloodpressure level, with a target systolic blood pressure of less than 140 mm Hg within 1 hour, was nonsignificantly lower than the rate among those assigned to guideline-recommended treatment, with a target systolic blood pressure of less than 180 mm Hg, with the use of a variety of antihypertensive medications (absolute difference, 3.6 percentage points; P = 0.06). 5 We designed the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-2) trial 6 to determine the efficacy of rapidly lowering the systolic blood-pressure level in patients in an earlier time window after symptom onset than that evaluated in previous trials. 4,5,7 The trial was based on evidence that hematoma expansion and the rate of subsequent death or disability might be reduced with very early and more aggressive reduction in the systolic blood-pressure level 8,9 among persons at high risk owing to a high systolic blood-pressure level (≥170 mm Hg10 to ≥200 mm Hg 11 ) at presentation.…”

Emerging experimental therapies for intracerebral hemorrhage: targeting mechanisms of secondary brain injury

“…8, 37 Early administration of hemostatic agents 46,47 and meticulous blood pressure control 1,2, 59,60 have been used to limit hematoma expansion. Large studies have examined the impact of reducing clot burden and mass effect through early surgical evacuation and catheter hematoma aspiration.…”

Treatment Targets in Intracerebral Hemorrhage

“…The primary outcome measure is death or disability (mRS, 4-6) at day 90. The study began in 2010 and plans to enroll 1280 patients [69].…”