ATACH II

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Qureshi A, et al. "Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage". The New England Journal of Medicine. 2016. :.
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Clinical Question

In patients with spontaneous intra-cranial hemorrhage with volume of <60 cm3 and a Glasgow Coma Scale (GCS) score of >4/15, does intensive systolic blood pressure control with IV nicardipine to a target of 110 to 139 mm Hg improve disability or lower morality when compared to a standard target of 140 to 179 mm Hg?

Bottom Line

In patients with spontaneous intra-cranial hemorrhage with volume of <60 cm3 and a Glasgow Coma Scale (GCS) score of >4/15, there is no differences in mortality or morbidity in patients receiving intensive blood pressure control compared to standard blood pressure control.

Major Points

Although less common than ischemic stroke, spontaneous intracranial hemorrhage (ICH) is often associated with more severe disability and higher mortality. Hemorrhages in deep brain structures are more frequently associated with sub-optimally controlled hypertension while lobar hemorrhages should trigger consideration for cerebral amyloid angiopathy.

Blood pressure is often elevated acutely after ICH [1] and the presence of elevated blood pressure has been associated with a number of poor outcomes including increased hematoma expansion, mortality and morbidity [2][3][4]. One area of contention in the medical management of ICH is the optimal blood pressure target acutely after spontaneous ICH. The last large scale RCT to influence guideline recommendations prior to ATACH II is INTERACT 2 which randomized patients to SBP targets of either less than 140 mmHg or less than 180 mmHg. The primary end point (death or major disability, defined as a Modified Rankin Scale Score of >3) narrowly missed significance (P=0.06) but ordinal analysis of scores on the modified Rankin scale and the EQ-5D scale were both significant on secondary end-point analysis.

With that in mind, the fact that ATACH II found no differences in death or major disability in those randomized to standard vs. intensive SBP control after acute spontaneous ICH may be due to differences in its study design. ATACH II used only IV nicardipine while INTERACT 2 allowed clinicians to selected the anti-hypertensive agents of their choice. ATACH II also looked at intensive control for only the first 24 hours after randomization while INTERACT 2 sought to control pressure for 7 days after randomization. It should also be noted that the mean minimum systolic blood pressure in the standard treatment group in ATACH II was 141 mmHg, at the lower limits recommended by current guidelines and the mortality and significant mortality rate in the standard treatment group (37.7%) is much lower than reported in previous ICH trials (~60%) [5] [6].

Guidelines

AHA/ASA Guidelines for the Management of Spontaneous Intracerebral Hemorrhage (updated 2015, adapted) [7] has not been changed by the results of this study

  • For ICH patients presenting with SBP between 150 and 220 mm Hg and without contraindication to acute BP treatment, acute lowering of SBP to 140mm Hg is safe (Class I; Level of Evidence A) and can be effective for improving functional outcome (Class IIa; Level of Evidence B).
  • For ICH patients presenting with SBP >220 mm Hg, it may be reasonable to consider aggressive reduction of BP with a continuous intravenous infusion and frequent BP monitoring (Class IIb; Level of Evidence C).

Design

  • Multicenter, two group open label randomization, blinded assessment of primary outcome
  • N=1000
    • Intensive control, n=500
    • Standard control, n=500
  • Setting: 173 centers in 7 countries
  • Enrollment: Jan 2011-Jan 2016
  • Follow-up: 3 months
  • Primary outcome: death or disability at 3 months post randomization

Population

Inclusion Criteria

  • Age >18 at randomization
  • Ability to receive IV nicardipine within 4.5 hours of symptom onset
  • Total Glasgow Coma Scale (GCS) score 5 or greater at time of emergency department (ED) arrival
  • International normalized ratio (INR) value < 1.5
  • CT scan demonstrates intraparenchymal bleed with volume measurement <60 cc
  • For subjects randomized prior to IV antihypertensive administration: SBP >180 mmHg at the time of randomization
  • For subjects randomized after IV antihypertensive administration: SBP >180 mmHg prior to IV antihypertensive treatment AND WITHOUT SBP reduction to below 140 mmHg at the time of randomization
  • Ability to obtain informed consent from subject, legally authorized representative, or next of kin

Exclusion Criteria

  • ICH thought to be non-spontaneous and due to previously known neoplasms, arteriovenous malformation (AVM), aneurysms or trauma
  • ICH located in infratentorial regions
  • Associate Intraventricular hemorrhage (IVH) with blood completely fills one lateral ventricle or more than half of both ventricles
  • Patient to receive immediate surgical evacuation
  • Current pregnancy, 30 days post-partum or patients with active lactation
  • Use of dabigatran within the last 48 hours
  • A platelet count less than 50,000
  • Known sensitivity to nicardipine
  • Pre-morbid disability requiring assistance in ambulation or activities of daily living
  • Subject's living will precludes aggressive ICU management
  • Subject is participating in another ongoing clinical trial

Baseline Characteristics

Demographic given for intensive BP treatment group, standard BP group similar due to adequate randomization

  • Age — yr: 62±13.1
  • Male sex — no. (%): 304 (60.8)
  • Race — no. (%):
    • Asian: 277 (55.4)
    • Black: 73 (14.6)
    • White: 142 (28.4)
    • Other or unknown: 8 (1.6)
  • Hispanic ethnic group — no. (%): 38 (7.6)
  • Recruited at site in Asia — no. (%): 264 (52.8)
  • Glasgow Coma Scale score — no. (%):
    • 3–11: 73 (14.6)
    • 12–14: 152 (30.4)
    • 15: 275 (55.0)
  • Systolic blood pressure at presentation in ED — mmHg: 200±27.1
  • Median NIHSS score (range): 11 (0–40)
  • Intracerebral hematoma volume >30 cc — no./total no. (%): 45/496 (9.1)
  • Median intracerebral hematoma volume (range) — cc: 10.3 (2.3–85.2)
  • Intraventricular hemorrhage — no./total no. (%): 122/496 (24.6)
  • Location of hemorrhage — no./total no. (%) numbers given for standard SBP group vs. intensive SBP group:
    • Thalamus: 193/496 (38.9) vs. 180/492 (36.6)
    • Basal ganglia: 255/496 (51.4) vs. 251/492 (51.0)
    • Cerebral lobe: 48/496 (9.7) vs. 60/492 (12.2)
    • Cerebellum 0/496: vs. 1/492 (0.2)

Interventions

  • Patients were randomized to systolic blood pressure (SBP) targets of 140 to 179 mm Hg in the standard-treatment group and systolic blood pressure of 110 to 139 mm Hg in the intensive-treatment group for 24 hours after randomization.
    • First line anti-hypertensive agent used was IV nicardipine: initiated at a dose of 5 mg per hour, which was then increased by 2.5 mg per hour every 15 minutes as needed, up to a maximum dose of 15 mg per hour.
    • If SBP not at target after maximum dose of nicardipine for 30 minutes, IV labetalol was used.
    • In countries where labetalol was not available, IV diltiazem or urapidil was used.

Outcomes

Outcomes are given intensive treatment vs. standard treatment, LR reported here are adjusted likelihood ratios are for age, baseline Glasgow Coma Scale (GCS) score, and the presence or absence of intraventricular hemorrhage at baseline. Unajusted LR can be found in the original paper.

Primary Outcome

  • Primary outcome: death or disability — no./total no. (%): 186/481 (38.7) vs. 181/480 (37.7) (LR 1.04, 95% CI 0.85 to 1.27, P=0.72)
  • Death — no. (%): 33 (6.6) vs. 34 (6.8) (LR 0.99, 95% CI 0.61 to 1.60, P=0.97)

Secondary Outcomes

  • Mean minimum systolic blood pressure 2 hours after treatment: 128.9±16 mmHg vs. 141.1±14.8 mmHg
  • Hematoma expansion (an increase of 33% or more in the hematoma volume from baseline to 24 hours) — no./total no. (%): 85/450 (18.9) vs. 104/426 (24.4) (LR 0.78, 95%CI 0.58 to 1.03, P=0.08)
  • Neurologic deterioration within 24 hr (decrease in GCS>1 or increase in NIHSS score >3 that persists for at least 8 hours) — no. (%): 55 (11.0) vs. 40 (8.0) (LR 1.39, 95% CI 0.92 to 2.09, P=0.11)

Subgroup Analysis

Subgroup analysis conducted for GCS at presentation, presence of intra-ventricular hemorrhage at presentation, baseline hematoma size and location, achievement of SBP target within 2 hours of treatment, diagnosis of DM2, sex, ethnicity and Asian enrollment center showed no significant interactions for primary outcome.

Adverse Events

Detailed definition of adverse events available in supplementary Appendix

  • Treatment-related serious adverse event within 72 hr — no. (%): 8 (1.6) vs. 6 (1.2) (LR 1.37, 95% CI 0.47 to 3.95, P=0.56)
  • Any serious adverse event within 3 mo— no. (%): 128 (25.6) vs. 100 (20.0) (LR 1.30, 95% CI 1.00 to 1.69, P=0.05)
  • Hypotension within 72 hr — no. (%): 6 (1.2) vs. 3 (0.6) (LR 1.96, 95% CI 0.49 to 7.87, P=0.34)
  • Any renal AE within 7 days — no. (%): 45 (9.0%) vs. 20 (4.0%) (LR 2.32, 95% CI 1.37 to 3.94, P=0.0018)
  • Any cardiac AE within 7 days — no. (%): 57 (11.4%) vs. 42 (8.4%) (LR 1.40, 95% CI 0.94 to 2.08, P= 0.1004)

Criticisms

  • Unlike prior studies like INTERACT 2, the use of IV nicardipine exclusively as a primary anti-hypertensive agent makes the study less applicable at centers where the agent is not routinely available
  • 50% Asian population with majority of deep ICH compared to more lobar distribution may limit application to other ethnicity

Funding

  • Funded by the National Institute of Neurological Disorders and Stroke and the National Cerebral and Cardiovascular Center

Further Reading

  1. Qureshi AI et al. Prevalence of elevated blood pressure in 563,704 adult patients with stroke presenting to the ED in the United States. Am J Emerg Med 2007. 25:32-8.
  2. Zhang Y et al. Blood pressure and clinical outcome among patients with acute stroke in Inner Mongolia, China. J. Hypertens. 2008. 26:1446-52.
  3. Rodriguez-Luna D et al. Impact of blood pressure changes and course on hematoma growth in acute intracerebral hemorrhage. Eur. J. Neurol. 2013. 20:1277-83.
  4. Sakamoto Y et al. Systolic blood pressure after intravenous antihypertensive treatment and clinical outcomes in hyperacute intracerebral hemorrhage: the stroke acute management with urgent risk-factor assessment and improvement-intracerebral hemorrhage study. Stroke 2013. 44:1846-51.
  5. Mayer SA et al. Recombinant activated factor VII for acute intracerebral hemorrhage: US phase IIA trial. Neurocrit Care 2006. 4:206-14.
  6. Lyden PD et al. Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: the CHANT Trial. Stroke 2007. 38:2262-9.
  7. Hemphill JC, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2015 May 28;STR.0000000000000069.