INTERACT 2

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Anderson CS, et al. "Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage". The New England Journal of Medicine. 2015. 368(25):2355-2365.
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Clinical Question

In patients with spontaneous intracerebral hemorrhage (ICH), does intensive blood pressure lowering (target systolic BP <140 mm Hg within 1 hour) reduce the risk of death or severe disability as compared to guideline-recommended treatment (target systolic BP <180 mm Hg)?

Bottom Line

In patients with intracerebral hemorrhage intensive blood pressure lowering did not reduce the risk of death or severe disability.

Major Points

The Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT2) determined the safety and efficacy of early intensive blood pressure (BP) lowering in patients with intracerebral hemorrhage. In the trial, 2839 patients who had a spontaneous intracerebral hemorrhage and elevated systolic BP were randomized to receive intensive blood pressure lowering treatment (target systolic BP <140 mm Hg within 1 hour) or guideline-recommended treatment (target systolic BP <180 mm Hg).

The trial results showed that intensive blood pressure lowering did not reduce the risk of death or severe disability.

The Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II is an ongoing trial with a similar clinical question to the INTERACT.[1] The trial is expected to be completed in 2016.

Guidelines

AHA/ASA Guidelines for the Management of Spontaneous Intracerebral Hemorrhage (2015 update, adapted)[2]

  • 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, prospective, randomized, open-treatment, blinded trial
  • N=2,839
    • intensive-treatment (n=1,403)
    • guideline-recommended (standard-treatment) (n=1,436)
  • Setting: 144 hospitals in 21 countries
  • Enrollment: 2008 to 2012
  • Mean follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary outcome: death or major disability
    • Major disability: A score of 3 to 5 on the modified Rankin scale at 90 days after randomization

Population

Inclusion Criteria

Presented elsewhere[3]

  • age ≥18 years
  • acute stroke syndrome due to spontaneous ICH, as confirmed by CT or MRI
  • ≥2 systolic BP of ≥150 and ≤220 mmHg, recorded ≥2 minutes apart
  • able to commence BP lowering within 6 hours after the onset of ICH

Exclusion Criteria

  • contraindication to intensive BP lowering (eg, severe carotid, vertebral or cerebral arterial stenosis, known Moya Moya disease or Takayasu's arteritis, high-grade stenotic valvular heart disease or severe renal failure)
  • indication to intensive BP lowering (eg, systolic BP >220 mmHg, hypertensive encephalopathy, or aortic dissection)
  • the ICH is secondary to a structural abnormality in the brain or recent thrombolysis
  • ischaemic stroke within the last 30 days
  • high likelihood of death within the next 24 hours
  • existing dementia or significant pre-stroke disability
  • planned early surgical evacuation of the haematoma
  • concomitant illness that may interfere with outcome assessments and follow-up
  • previously participated in INTERACT2 or currently participating in another investigational drug trial
  • high likelihood of not adhering to the study treatment and follow-up

Baseline Characteristics

This describes the patients in the intensive-treatment group

  • Mean age: 63.0±13.1 years
  • Male: 64.2%
  • Mean systolic BP: 179±17 mmHg
  • Mean diastolic BP: 101±15 mmHg
  • Severity of stroke, as assessed by:
    • Median National Institutes of Health Stroke Scale (NIHSS) score: 10
    • Median GCS: 14
  • History of hypertension: 72.4%
  • Prior intracerebral hemorrhage: 8.2%
  • Prior ischemic or undifferentiated stroke: 11.2%
  • Diabetes mellitus: 11.1%
  • Use of warfarin: 3.6%
  • Use of antiplatelet agent: 8.8%
  • Median baseline hematoma volume: 11 ml
  • Deep location of hematoma: 83.8%

Interventions

Intensive-treatment group

  • Treatment goal of systolic BP <140 mm Hg within 1 hour after randomization and of maintaining this level for the next 7 days
  • The goal was selected based on results from the INTERACT1 study.[4]
  • the intravenous BP-lowering protocol was based on the local availability of medications (eg, urapidil, labetolol, hydralazine, metoprolol and nicardipine)
  • IV treatment was stopped if systolic BP <130 mm Hg

Standard-treatment group

  • To receive BP lowering treatment if systolic BP >180 mm Hg, according to the American Heart Association and European Stroke Organization guidelines.[5][6]
  • BP lowering modalities at discretion of treating physician

In both groups

  • oral antihypertensive therapy taken before randomization were continued
  • oral antihypertensive therapy was recommended for all patients within 7 days with the target systolic of BP<140 mmHg for secondary prevention

Outcomes

Comparisons are intensive therapy vs. standard therapy

Primary Outcomes

Death or major disability
52.0% vs. 55.6% (OR 0.87; 95% CI 0.75-1.01; P=0.06)

Secondary Outcomes

Physical function across all seven levels of the modified Rankin scale
the intensive treatment group had better functional outcomes, as suggested by a lower modified Rankin scores (OR for greater disability 0.87; 95% CI 0.77-1.00; P=0.04)
all-cause mortality
11.9% vs. 12.0% (OR 0.99; 95% CI 0.79-1.25; P=0.96)
health-related quality of life
data expressed as mean [±SD] European Quality of Life–5 Dimensions utility score[7]
0.60±0.39 vs. 0.55±0.40 (P=0.002)

Subgroup Analysis

no evidence of heterogeneity in the effect of treatment in any prespecified subgroup

Adverse Events

Neurologic deterioration in first 24 hr
14.5% vs. 15.1% (OR 0.95; 95% CI 0.77-1.17; P=0.62)
severe hypotension requiring treatment with intravenous fluids or vasopressor agent
0.5% vs. 0.6% (P=NS)
Nonfatal serious adverse events
23.3% vs. 23.6% (P=0.92)

Criticisms

  • Different antihypertensive medications were used, and this introduced complexity in assessing how treatment effects varied across different agents.[8] For example, patients (16.2%) in the intensive-treatment group received a calcium-channel blocker including Nimodipine. This agent is known to reduce adverse outcomes in subarachnoid hemorrhage. Hence it's unclear how much of the treatment effect seen with intensive-treatment can be attributed to the pleiotropic effect of the agent.[9]
  • The study was unblinded. This may have led to differences in management strategies, which in turn may confound the outcomes.[8]
  • The improvement in functional outcome seen was based on an ordinal analysis of modified Rankin scale scores. The analysis was considered only after the trial had commenced.[9][10] The mechanism of this improvement is also unclear.[9]
  • Several factors may limit the generalizability of the trial results:[11]
    • More than two thirds of the participants were from China.
    • The most common BP-lowering agent was IV urapidil (32.5% in the intensive-treatment group). The more common IV agents used in the United States were infrequently used (<16% in the intensive-treatment group).[12]
    • The majority of the patients (72.4%) had hypertension, and 83.8% had deep, and small volume hematomas
  • Data on intracranial pressure or cerebral perfusion pressure were not reported. Patients with elevated intracranial pressure may require additional monitoring modalities to individualized target BP levels.[11] Variability of intracranial pressure may also predict neurologic outcome.[13]
  • Only one third of the patients achieved target BP within 1 hour.[2]

Funding

The National Health and Medical Research Council (NHMRC) of Australia

Further Reading

  1. Qureshi AI, Palesch YY. Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II: Design, Methods, and Rationale. Neurocrit Care. 2011 May 28;15(3):559–76.
  2. 2.0 2.1 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.
  3. Delcourt, C., Huang, Y., Wang, J., Heeley, E., Lindley, R., Stapf, C., Tzourio, C., Arima, H., Parsons, M., Sun, J., Neal, B., Chalmers, J., Anderson, C. and for the INTERACT2 Investigators (2010), The second (main) phase of an open, randomised, multicentre study to investigate the effectiveness of an intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT2). International Journal of Stroke,5: 110–116. doi: 10.1111/j.1747-4949.2010.00415.x
  4. Anderson CS, Huang Y, Arima H, et al. Effects of early intensive blood pressure-lowering treatment on the growth of hematoma and perihematomal edema in acute intracerebral hemorrhage: the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT). Stroke 2010;41:307-312
  5. Broderick J, Connolly S, Feldmann E, Hanley D, Kase C, Krieger D, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults 2007 Update: A Guideline From the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007 6;38(6):2001–23.
  6. Steiner T, Kaste M, Katse M, Forsting M, et al. Recommendations for the management of intracranial haemorrhage - part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovasc Dis. 2006;22(4):294–316.
  7. Rabin R, Charro F de. EQ-SD: a measure of health status from the EuroQol Group. Annals of Medicine. 2001 Jan 1;33(5):337–43.
  8. 8.0 8.1 Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013;368:2355-2365
  9. 9.0 9.1 9.2 Blood-Pressure Lowering in Acute Intracerebral Hemorrhage. N Engl J Med. 2013; 369:1273-1275
  10. Graber MA, Dachs R, Endres J. Is intensive blood pressure control beneficial in patients with acute intracerebral hemorrhage? Am Fam Physician. 2014. 15;89(2):120–1.
  11. 11.0 11.1 Frontera JA. Blood Pressure in Intracerebral Hemorrhage — How Low Should We Go? N Engl J Med. 2013;368:2426-242
  12. Basile JN, Bloch MJ. Analysis of recent papers in hypertension treatment of hypertension in the setting of acute intracerebral hemorrhage: still no clear answer on the best BP level to intervene or what BP goal to achieve. J Clin Hypertens (Greenwich). 2014 Jan;16(1):1–3.
  13. Tian Y, Wang Z, Jia Y, et al. Intracranial pressure variability predicts short-term outcome after intracerebral hemorrhage: A retrospective study. Journal of the Neurological Sciences. 2013. 15;330(1–2):38–44.