JOURNAL REVIEW

Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage

(INTERACT-2 trial)

• Craig S. Anderson, Emma Heeley, Yining Huang et al• Published in NEJM June 2013

• INTERACT – INTEnsive Blood pressure Reduction in Acute Cerebral Hemorrhage Trial

• INTERACT 1 Trial :– Results published in Lancet Neurology, May 2008.– Study enrolled 404 patients from 44 hospitals in

Australia, China and Korea from November 2005 to April 2007.

INTERACT 2 TRIAL :

• AIM - To establish the effects of a management policy of early intensive BP lowering on death and disability in patients with acute spontaneous, primary, ICH and co-existing elevated BP compared to a more conservative BP management policy.

• Study used a similar design to the pilot study - INTERACT1 – undertaken in 44 sites in Australia, China and South Korea during 2005-2007.

• An international, multi-centre, prospective, open label, blinded outcome, randomised, controlled trial involving patients with acute ICH recruited from approximately 140 sites in the world.

• INCLUSION CRITERIA :-– Patients with CT-confirmed acute ICH within 6 hours of

onset were eligible if they had a sustained elevated systolic BP level (≥150 to ≤220 mmHg) and where an intensive BP lowering management strategy and active ancillary care are available.

• EXCLUSION CRITERIA :-– Clear indication to BP lowering (eg very high BP >220 mmHg or

hypertensive encephalopathy or Aortic Dissection) – A structural cause for ICH– a contraindication to intensive BP lowering (eg known severe

carotid stenosis or uncontrolled heart failure)– the attending clinician considers the patient to be unlikely to benefit

from any therapy due to existing severe illness or medical condition (eg advanced dementia, known serious pre-stroke disability) or because they have a very high likelihood of death within 24 hours (ie GCS score 3-5) or massive ICH with major cerebral midline shift

– there is concomitant medical illness that would interfere with outcome assessments and follow-up; and

– Early surgical removal of the haematoma evacuation has been planned.

• Written informed consent was obtained from each patient or legal surrogate (before randomization or as soon as possible afterward).

• Patients were randomised via a 24-hour central internet-based randomisation system to either : – Intensive or – Conservative management of BP.

• Treatment was to be started as soon as possible after randomisation (eg in the emergency department) and to be continued in a monitored facility (ie ICU, high dependency unit, or stroke unit) for all randomised patients.

• Intensive BP lowering – – started on a standardised treatment regime commencing

with intravenous and then changed when feasible to oral (or via a nasogastric tube) agent(s).

– The treatment goal was to achieve a systolic BP goal (<140 mmHg) within one hour of commencing the randomised treatment.

– The second goal was to maintain the systolic BP to 140 mmHg or less or at least 7 days in hospital, and subsequently on discharge and for 90 days post-randomisation.

– Specific treatment protocols were developed for each participating region/centre based on the availability of BP lowering agents for routine use.

• Conservative BP lowering - – patients allocated to this group received BP management

based on American Heart Association (AHA) guidelines. – In this group, the threshold to be considered for the

initiation of treatment was a systolic BP ≥180 mmHg.

• For both groups, patients was started on an oral anti-hypertensive agent by day 7 or discharge from acute care hospital, with a long-term target systolic BP of 140 mmHg, as per secondary stroke prevention guidelines.

• DATA COLLECTION AND FOLLOW UP –– Demographic and clinical characteristics were recorded at

the time of randomisation.

– The severity of the stroke was assessed with the use of the GCS and the NIHSS scale at baseline, at 24 hours, and at 7 days (or at the time of discharge, if that occurred before 7 days).

– Follow-up data collected on four occasions: 24 hours and 7 days (or at the time of death or hospital discharge, if this should occur before day 7), and 28 days and 90 days, with the latter two assessments carried out either in-person or over the telephone.

• Brain CT (or MRI) was performed according to standard techniques at baseline (to confirm the diagnosis) in all patients, and at 24±3 hours in a subgroup of patients who were being treated at sites at which repeat scanning was either part of routine practice or approved for research.

• The clinical assessments to be undertaken by a person who was not involved in the initial treatment of the patient and kept blind to the treatment allocation.

• Data collection and trial management was done by an established internet-based system.

Outcomes

• Primary outcome:

– Combined endpoint of death and dependency/major disability at the end of follow-up.

– Major disability was defined as a score of 3 to 5 on the modified Rankin scale at 90 days after randomization.

– Secondary outcome: – To assess efficacy of the primary outcome in those

patients treated within 4 hours of ICH onset. – The key secondary outcome was redefined during the

study as physical function across all seven levels of the modified Rankin scale.

– Other secondary outcomes: To determine effects of treatment on

(a) physical function, health-related quality of life, recurrent stroke and other vascular events, duration of hospitalisation, and requirement for permanent residential care, and

(b) other serious adverse events.

• The safety outcomes of primary interest were early neurologic deterioration (defined as an increase from baseline to 24 hours of 4 or more points on the NIHSS or a decrease of 2 or more points on the GCS) and episodes of severe hypotension with clinical consequences that required corrective therapy with intravenous fluids or vasopressor agents.

• The data were analyzed using SAS software, version 9.2.

RESULTS• Study conducted from October 2008 to August 2012

• A total of 2839 participants (mean age = 63.5 years; 62.9% men) were enrolled at 144 hospitals in 21 countries.

• 1403 participants were randomly assigned to receive early intensive treatment to lower their blood pressure, and 1436 were assigned to receive guideline-recommended treatment.

• The baseline characteristics were balanced between the two groups.

• The primary outcome was determined for 1382 of the participants (98.5%) in the intensive-treatment group and for 1412 (98.3%) in the standard-treatment group.

• The median time from the onset of the intracerebral hemorrhage to the initiation of intravenous treatment was shorter in the intensive-treatment group(4.0 hours [interquartile range, 2.9 to 5.1]) than in the standard therapy group ( 4.5 hours [interquartile range, 3.0 to 7.0] P<0.001).

• The median time from randomization to the initiation of treatment was also shorter in the intensive-treatment group (6 minutes [inter quartile range, 0 to 39] vs. 19 minutes [interquartile range, 0 to 167]).

• More patients in the intensive-treatment group than in the standard treatment group received two or more intravenous agents to lower their blood pressure (26.6% vs. 8.1%, P<0.001).

• The mean systolic blood-pressure levels differed significantly between the two groups from 15 minutes to day 7 after randomization; – at 1 hour, the mean systolic blood pressure was 150 mm

Hg in the intensive-treatment group (with 462 patients [33.4%] achieving the target blood pressure of <140 mm Hg) as compared with 164 mm Hg in the standard-treatment group (a difference of 14 mm Hg, P<0.001).

CLINICAL OUTCOME & ADVERSE EVENTS :

• At 90 days, 719 of the participants (52.0%) in the intensive-treatment group, as compared with 785 (55.6%) in the standard-treatment group, had a poor outcome (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06).

• The ordinal analysis showed a significant favorable shift in the distribution of scores on the modified Rankin scale with intensive blood-pressure lowering treatment.

• Stastical analyses also showed consistency in the treatment effect with respect to the primary and key secondary outcomes.

• While assessing health related quality of life, participants in the intensive-treatment group reported fewer problems and had significantly better overall health-related quality of life at 90 days than did those in the standard-therapy group.

• The rate of death from any cause was similar in the intensive-treatment group and the standard-treatment group (11.9% and 12.0%, respectively)

• There were no significant differences between the two groups in any of the other outcomes studied.

• The numbers of serious adverse events, including episodes of severe hypotension (which occurred in <1% of the participants), were also balanced between the two groups.

HAEMATOMA OUTCOMES :

• The mean hematoma volumes were 15.7±15.7 ml and 15.1±14.9 ml in the two groups, respectively, at baseline and 18.2±19.1 ml and 20.6±24.9 ml, respectively, at 24 hours.

• The difference in hematoma growth between the groups in the 24 hours after baseline was not significant.

DISCUSSION• Hypertension is a well established as the major risk factor for

ICH, with several large-scale observational studies demonstrating that BP levels are positively and continuously associated with risks of ICH.

• The association between hypertension and ICH risk appears to be much stronger than that for ischaemic stroke.

• Also evidence that BP levels are strongly and positively associated with the long-term risks of recurrent stroke for both haemorrhagic and ischaemic events.

• In a systematic review, systolic BP elevations of 10 mmHg were associated with a 42% (95% confidence interval [95% CI] 39-44%) increase in the risk of haemorrhagic stroke.

• The relative risk of ICH in hypertensive individuals is 2-3 times that of non-hypertensive individuals.

• In addition, among hypertensive individuals, those who have ceased taking medication appear to be at significantly greater risk of ICH.

• Modern neuroimaging studies indicate that continued bleeding and expansion of the haematoma of ICH occurs in up to one-third of patients within several hours of onset, and probably over 3 to 24 hours in another 10%.

• Further neurological deterioration may occur over several days secondary to the adverse effects of oedema and inflammation in the peri-haematomal region.

• In this trial involving patients with intracranial hemorrhage, early intensive lowering of blood pressure, as compared with the more conservative level of blood pressure control currently recommended in guidelines, did not result in a significant reduction in the rate of the primary outcome of death or major disability.

• However, in an ordinal analysis of the primary outcome, in which the statistical power for assessing physical functioning was enhanced, there were significantly better functional outcomes among patients assigned to intensive treatment to lower their blood pressure than among patients assigned to guideline recommended treatment.

• Furthermore, there was significantly better physical and psychological well-being among patients who received intensive treatment.

LIMITATIONS OF THE STUDY :-• The option to use a range of available drug therapies introduced

complexity in assessing the ways in which the effects may have varied across different agents.

• Although established scales and objective criteria were used, some bias may have been introduced in the assessment of key outcomes.

• Third, the difference in the blood-pressure levels achieved between the two groups may have been attenuated by the concomitant use of additional agents with blood pressure lowering properties (e.g., mannitol).

• Heterogeneity in intensity of medical care in subjects between sites can affect the rates of death and disability

CONCLUSIONS :• Early intensive lowering of blood pressure did not result in a

significant reduction in the rate of the primary outcome of death or major disability.

• But an ordinal analysis of scores on the modified Rankin scale did suggest that intensive treatment improved functional outcomes.

• Intensive lowering of blood pressure was not associated with an increase in the rates of death or serious adverse events.

ASA GUDELINES 2010• Until ongoing clinical trials of BP intervention for ICH are

completed, physicians must manage BP on the basis of the present incomplete efficacy evidence.

• In patients presenting with a systolic BP of 150 to 220 mm Hg, acute lowering of systolic BP to 140 mm Hg is probably safe (Class IIa; Level of Evidence: B).

ASA GUIDELINES 2015• For ICH patients presenting with SBP between 150 and 220

mm Hg and without contraindication to acute BP treatment, acute lowering of SBP to 140 mm Hg is safe (Class I; Level of Evidence A) and can be effective for improving functional outcome (Class IIa; Level of Evidence B). (Revised from the previous guideline)

• 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). (New recommendation)

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