Journal Review INTERACT 2

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)

Journal Review INTERACT 2

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Journal Review INTERACT 2